IMMUNOTHERAPEUTIC AGENTS AND THEIR USE IN THE REDUCTION OF CYTOKINE LEVELS

Description

[0001] This invention relates to a method of reducing the level of cytokines and their precursors in mammals and to compounds and compositions useful therein. In particular, the invention pertains to a class of compounds which mediate the action of phosphodiesterases, particularly PDE III and PDE IV, and the formation of TNFα and NFκB.

[0002] Tumor necrosis factor alpha, (TNFα) is a cytokine which is released primarily by mononuclear phagocytes in response to immunostimulators. When administered to animals or humans, TNFα can cause inflammation, fever, cardiovascular effects, hemorrhage, coagulation, and acute phase responses similar to those seen during acute infections and shock states.

[0003] The nuclear factor κB (NFκB) is a pleiotropic transcriptional activator (Lenardo, et al., Cell 1989, 58, 227-29) which has been implicated in a variety of disease and inflammatory states. NFκB is thought to regulate cytokine levels including, but not limited to, TNFα and to be an activator of HIV transcription (Dbaibo et al., J. Biol. Chem. 1993, 17762-66; Duh et al., Proc. Natl. Acad. Sci. 1989, 86, 5974-78; Bachelerie et al., Nature 1991, 350, 709-12; Boswas et al., J Acquired Immune Deficiency Syndrome 1993, 6, 778-786; Suzuki et al., Biochem. And Biophys. Res. Comm. 1993, 193, 277-83; Suzuki et al., Biochem. And Biophys. Res Comm. 1992, 189, 1709-15; Suzuki et al., Biochem. Mol. Bio. Int. 1993, 31(4), 693-700; Shakhov et al. 1990, 171, 35-47; and Staal et al., Proc. Natl. Acad. Sci. USA 1990, 87, 9943-47). Thus, inhibition of NFκB binding can regulate transcription of cytokine gene(s) and through this modulation and other mechanisms be useful in the inhibition of a multitude of disease states. TNFα and NFκB levels are influenced by a reciprocal feedback loop.

[0004] Many cellular functions are mediated by levels of adenosine 3',5'-cyclic monophosphate (cAMP). Such cellular functions can contribute to inflammatory conditions and diseases including asthma, inflammation, and other conditions (Lowe and Cheng, Drugs of the Future, 17(9), 799-807, 1992). It has been shown that the elevation of cAMP in inflammatory leukocytes inhibits their activation and the subsequent release of inflammatory mediators, including TNFα and NFκB. Increased levels of cAMP also leads to the relaxation of airway smooth muscle. The primary cellular mechanism for the inactivation of cAMP is the breakdown of cAMP by a family of isoenzymes referred to as cyclic nucleotide phosphodiesterases (PDE), of which seven are known. It is recognized, for example, that the inhibition of PDE type IV is particularly effective in both the inhibition of inflammatory mediator release and the relaxation of airway smooth muscle. Thus, compounds which inhibit PDE IV exhibit the desirable inhibition of inflammation and relaxation of airway smooth muscle with a minimum of unwanted side effects, such as cardio-vascular or anti-platelet effects. It is now known that inhibition of TNFα production is a consequence of inhibition of PDE IV. L.J. Lombardo, Current Pharmaceutical design, 1, 255-268 (1995).

[0005] Excessive or unregulated TNFα production has been implicated in a number of disease conditions. These include endotoxemia and/or toxic shock syndrome {Tracey et al., Nature 330, 662-664 (1987) and Hinshaw et al., Circ. Shock 30, 279-292 (1990)}; cachexia {Dezube et al., Lancet, 335 (8690), 662 (1990)}; and Adult Respiratory Distress Syndrome (ARDS) where TNFα concentrations in excess of 12,000 pg/milliliters have been detected in pulmonary aspirates from ARDS patients {Millar et al., Lancet 2 (8665), 712-714 (1989)}. Systemic infusion of recombinant TNFα also resulted in changes typically seen in ARDS {Ferrai-Baliviera et al., Arch. Surg. 124(12), 1400-1405 (1989)}.

[0006] TNFα also appears to be involved in bone resorption diseases, including arthritis where it has been determined that when activated, leukocytes will produce a bone-resorbing activity, and data suggests that TNFα contributes to this activity {Bertolini et al., Nature 319, 516-518 (1986) and Johnson et al., Endocrinology 124(3), 1424-1427 (1989)}. It has been determined that TNFα stimulates bone resorption and inhibits bone formation in vitro and in vivo through stimulation of osteoblast formation and activation in combination with inhibition of osteoblast function. Although TNFα may be involved in many bone resorption diseases, including arthritis, the most compelling link with disease is the association between production of TNFα by tumor or host tissues and malignancy associated hypercalcemia {Calci. Tissue Int. (US) 46 (Suppl.), S3-10 (1990)}. In Graft versus Host Reaction, increased serum TNFα levels have been associated with major complications following acute allogenic bone marrow transplants {Holler et al., Blood, 75(4), 1011-1016(1990)}.

[0007] Cerebral malaria is a lethal hyperacute neurological syndrome associated with high blood levels of TNFα and is the most severe complication occurring in malaria patients. Levels of serum TNFα correlated directly with the severity of the disease and the prognosis in patients with acute malaria attacks {Grau et al., N. Engl. J. Med. 320 (24), 1586-1591 (1989)}.

[0008] Macrophage-induced angiogenesis is known to be mediated by TNFα. Leibovich et al. {Nature, 329, 630-632 (1987)} showed TNFα induces in vivo capillary blood vessel formation in the rat cornea and the developing chick chorioallantoic membranes at very low doses and suggest TNFα is a candidate for inducing angiogenesis in inflammation, wound repair, and tumor growth. TNFα production also has been associated with cancerous conditions, particularly induced tumors {Ching et al., Brit. J. Cancer, (1955) 72, 339-343, and Koch, Progress in Medicinal Chemistry, 22, 166-242 (1985)}.

[0009] TNFα also appears to play a role in the area of chronic pulmonary inflammatory diseases. The deposition of silica particles leads to silicosis, a disease of progressive respiratory failure caused by a fibrotic reaction. Antibodies to TNFα completely blocked the silica-induced lung fibrosis in mice {Pignet et al., Nature, 344:245-247 (1990)}. High levels of TNFα production (in the serum and in isolated macrophages) have been demonstrated in animal models of silica and asbestos induced fibrosis {Bissonnette et al., Inflammation 13(3), 329-339 (1989)}. Alveolar macrophages from pulmonary sarcoidosis patients have also been found to spontaneously release massive quantities of TNFα as compared with macrophages from normal donors {Baughman et al., J. Lab. Clin. Med. 115(1), 36-42 (1990)}.

[0010] TNFα is also implicated in the inflammatory response which follows reperfusion, called reperfusion injury, and is a major cause of tissue damage after loss of blood flow {Vedder et al., PNAS 87, 2643-2646 (1990)}. TNFα also alters the properties of endothelial cells and has various pro-coagulant activities, such as producing an increase in tissue factor pro-coagulant activity and suppression of the anticoagulant protein C pathway as well as down-regulating the expression of thrombomodulin {Sherry et al., J. Cell Biol. 107, 1269-1277 (1988)}. TNFα has pro-inflammatory activities which together with its early production (during the initial stage of an inflammatory event) make it a likely mediator of tissue injury in several important disorders including but not limited to, myocardial infarction, stroke and circulatory shock. Of specific importance may be TNFα-induced expression of adhesion molecules, such as intercellular adhesion molecule (ICAM) or endothelial leukocyte adhesion molecule (ELAM) on endothelial cells {Munro et al., Am J. Path. 135 (1), 121-132 (1989)}.

[0011] TNFα blockage with monoclonal anti-TNFα antibodies has been shown to be beneficial in rheumatoid arthritis {Elliot et al., Int. J. Pharmac. 1995 17(2), 141-145}. High levels of TNFα are associated with Crohn's disease {von Dullemen et al., Gastroenterology, 1995 109(1), 129-135} and clinical benefit has been achieved with TNFα antibody treatment, thus confirming the importance of TNFα in the disease.

[0012] Moreover, it is now known that TNFα is a potent activator of retrovirus replication including activation of HIV-1. {Duh et al., Proc. Nal. Acad. Sci. 86, 5974-5978 (1989); Poll et al., Proc. Nat. Acad. Sci. 87, 782-785 (1990); Monto et al., Blood 79, 2670 (1990); Clouse et al., J. Immunol. 142, 431-438 (1989); Poll et al., AIDS Res. Hum. Retrovirus, 191-197 (1992)}. AIDS results from the infection of T lymphocytes with Human Immunodeficiency Virus (HIV). At least three types or strains of HIV have been identified, i.e., HIV-1, HIV-2 and HIV-3. As a consequence of HIV infection, T-cell mediated immunity is impaired and infected individuals manifest severe opportunistic infections and/or unusual neoplasms. HIV entry into the T lymphocyte requires T lymphocyte activation. Other viruses, such as HIV-1 and HIV-2, infect T lymphocytes after T cell activation and such virus protein expression and/or replication is mediated or maintained by such T cell activation. Once an activated T lymphocyte is infected with HIV, the T lymphocyte must continue to be maintained in an activated state to permit HIV gene expression and/or HIV replication. Cytokines, specifically TNFα, are implicated in activated T-cell mediated HIV protein expression and/or virus replication by playing a role in maintaining T lymphocyte activation. Therefore, interference with cytokine activity such as by prevention or inhibition of cytokine production, notably TNFα, in a HIV-infected individual aids in limiting the maintenance of T lymphocyte activation caused by HIV infection.

[0013] Monocytes, macrophages, and related cells, such as kupffer and glial cells, have also been implicated in maintenance of the HIV infection. These cells, like T cells, are targets for viral replication and the level of viral replication is dependent upon the activation state of the cells {Rosenberg et al., The Immunopathogenesis of HIV Infection, Advances in Immunology, 57 (1989)}. Cytokines, such as TNFα, have been shown to activate HIV replication in monocytes and/or macrophages {Poli et al. Proc. Natl. Acad. Sci., 87, 782-784 (1990)}, therefore, prevention or inhibition of cytokine production or activity aids in limiting HIV progression as stated above for T cells. Additional studies have identified TNFα as a common factor in the activation of HIV in vitro and has provided a clear mechanism of action via a nuclear regulatory protein found in the cytoplasm of cells (Osborn, et al., PNAS 86, 2336-2340). This evidence suggests that a reduction of TNFα synthesis may have an antiviral effect in HIV infections, by reducing the transcription and thus virus production.

[0014] AIDS viral replication of latent HIV in T cell and macrophage lines can be induced by TNFα {Folks et al., PNAS 86, 2365-2368 (1989)}. A molecular mechanism for the virus inducing activity is suggested by TNFα's ability to activate a gene regulatory protein (NFκB) found in the cytoplasm of cells, which promotes HIV replication through binding to a viral regulatory gene sequence (LTR) {Osborn et al., PNAS 86, 2336-2340 (1989)}. TNFα in AIDS associated cachexia is suggested by elevated serum TNFα and high levels of spontaneous TNFα production in peripheral blood monocytes from patients {Wright et al., J. Immunol. 141 (1), 99-104 (1988)}.

[0015] TNFα has been implicated in other viral infections, such as the cytomegalia virus (CMV), influenza virus, adenovirus, and the herpes family of viruses for similar reasons as those noted.

[0016] It is recognized that suppression of the effects of TNFα can be beneficial in a variety of conditions and in the past, steroids such as dexamethasone and prednisone as well as polyclonal and monoclonal antibodies {Beutler et al., Science 234, 470-474 (1985); WO 92/11383} have been employed for this purpose. Conditions in which the inhibition of TNFα is desirable include septic shock, sepsis, endotoxic shock, hemodynamic shock and sepsis syndrome, post ischemic reperfusion injury, malaria, mycobacterial infection, meningitis, psoriasis, congestive heart failure, fibrotic disease, cachexia, graft rejection, cancer, autoimmune disease, opportunistic infections in AIDS, rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis and other arthritic conditions, Crohn's disease, ulcerative colitis, multiple sclerosis, systemic lupus erythrematosis, ENL in leprosy, radiation damage, asthma, and hyperoxic alveolar injury.

[0017] The suppression of the action of NFκB in the nucleus can be useful in the treatment of a variety of diseases including but not limited to rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis, other arthritic conditions, septic shock, septis, endotoxic shock, graft versus host disease, wasting, Crohn's disease, ulcerative colitis, multiple sclerosis, systemic lupus erythrematosis, ENL in leprosy, HIV, AIDS, and opportunistic infections in AIDS.

[0018] International patent application no. WO 96/21435 discloses compounds for and method of inhibiting phosphodiesterase IV. The compounds possess improved PDE IV inhibition as compared to theophylline or rolipram as well as with improved selectivity with regard to PDE III inhibition.

[0019] International patent application no. WO 96/20926 discloses substituted imides as tumor necrosis factor a which can be used to combat cachexia, endotoxic shock and retrovirus replication. A typical compound disclosed is 2-phthalimido-3-(3',4'-dimethoxyphenyl) propane.

[0020] International patent application no. WO 94/14800 discloses styril derivatives which are active PDE IV inhibitors.

[0021] International patent publication no. 94/14742 discloses tri-substituted phenyl derivatives as phosphodiesterase inhibitors.

Detailed Description

[0022] The compounds of the present invention affect the levels of phosphodiesterases, TNFα and NFκB and the method involves the regulation of the levels of phosphodiesterases, TNFα and NFκB through the administration of compounds of the formula:

in which:

R²

is hydrogen, nitro, cyano, trifluoromethyl, carboethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino, alkyl of 1 to 6 carbon atoms, alkylidenemethyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms or halo; with the proviso that either R¹ is selected from a group consisting of alkoxy of 1 to 6 carbon atoms, cycloalkoxy of from 3 to 10 carbon atoms and cyclopentylidenemethyl, and R² is alkoxy of 1 to 6 carbon atoms; or, R³ is phenyl independently substituted at the 3- and 4-positions with alkoxy up to 10 carbon atoms or cycloalkoxy of up to 10 carbon atoms; and

R³

is (i) phenyl, substituted or unsubstituted with 1 or more substituents, each selected independently from a group consisting of nitro, cyano, halo, trifluoromethyl, carboethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, or carbamoyl substituted with alkyl of 1 to 3 carbon atoms, acetoxy, carboxy, hydroxy, amino, amino substituted with an alkyl of 1 to 5 carbon atoms, alkyl of up to 10 carbon atoms, cycloalkyl of up to 10 carbon atoms, alkoxy of up to 10 carbon atoms, cycloalkoxy of up to 10 carbon atoms, alkylidenemethyl of up to 10 carbon atoms, cycloalkylidenemethyl of up to 10 carbon atoms, phenyl or methylenedioxy; (ii) pyridine, substituted pyridine, 2- or 3- pyrrolidene, imidazole, naphthalene, or thiophene; (iii) cycloalkyl of 4 to 10 carbon atoms, unsubstituted or substituted with one or more substituents each selected independently from the group consisting of nitro, cyano, halo, trifluoromethyl, carboethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino, substituted amino, alkyl of 1 to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms, phenyl;

each of R⁴ and R⁵ taken individually is a hydrogen or R⁴ and R⁵ together are a carbon-carbon bond;
   wherein,

Y

is CN;

R¹

is R⁸, (CH₂)_nR⁸, OR⁸, CH=CHR⁸, or CH=C(R¹⁰)₂ with the proviso that R³ cannot be unsubstituted phenyl when R¹ is methyl and R² is hydroxy;

R⁸

is methyl or R⁹;

R⁹

is alkyl of 2 to 10 carbon atoms, monocycloalkyl of 3 to 10 carbon atoms, polycycloalkyl of up to 10 carbon atoms, benzocycloalkyl of up to 10 carbons atoms;

R¹⁰

together with the carbon atom to which they are attached form a monocycloalkyl or bicycloalkyl group of up to 10 carbon atoms;

n

is 1 to 3;

or, alternatively, when each of R⁴ and R⁵ taken individually is hydrogen;

Y

is -CON(R⁶)₂, -CO₂H, -CO₂R⁷;

R¹

is -R⁹, -(CH₂)_nR⁸, -OR⁹, -CH=CHR⁸, or -CH=C(R¹⁰)₂;

R⁶

is hydrogen or alkyl of 1 to 6 carbon atoms;

R⁷

is alkyl of 1 to 6 carbon atoms or benzyl; or,

Y

is COR⁷;

R¹

is -R⁸, (CH₂)_nR⁸, OR⁸, CH=CHR⁸, or CH=C(R¹⁰)₂ with the proviso that R¹ and R² cannot be -OMe when R³ is hydroxy substituted phenyl.

[0023] One preferred group are the compounds of Formula I in which Y is -CN or COR⁷; R¹ is R⁸, (CH₂)_nR⁸, OR⁸; R² is hydrogen, nitro, cyano, trifluoromethyl, carboethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms or halo and R³, R⁴, R⁵, and R¹⁰ are as therein defined.

[0024] A second preferred group of compounds are those of Formula I in which Y. is -CONR⁶R⁶, CO₂H or CO₂R⁷; R¹ is R⁹, (CH₂)_nR⁸, OR⁹; R² is hydrogen, nitro, cyano, trifluoromethyl, carboethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms or halo and R³, R⁴, R⁵, R⁶, R⁷ and R¹⁰ are as therein defined.

[0025] A third preferred group of compounds are those of Formula I in which R³ is (i) phenyl or naphthalene, unsubstituted or substituted with 1 or more substituents each selected independently from nitro, cyano, halo, trifluoromethyl, carbethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, or carbamoyl substituted with alkyl of 1 to 3 carbon atoms, acetoxy, carboxy, hydroxy, amino, amino substituted with an alkyl of 1 to 5 carbon atoms, alkyl or cycloalkyl of 1 to 10 carbon atoms, alkoxy or cycloalkoxy of 1 to 10 carbon atoms; or (ii) cycloalkyl of 4 to 10 carbon atoms, unsubstituted or substituted with one or more substituents each selected independently from the group consisting of nitro, cyano, halo, trifluoromethyl, carbethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino, substituted amino, alkyl of 1 to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms, or phenyl.

[0026] Particularly preferred nitriles or ketones are compound of the formula IIA and IIB:

wherein:

Y

is -CN or -COR⁷,

R¹

is R⁸, (CH₂)_nR⁸, OR⁸, CH=CHR⁸, or CH=C(R¹⁰)₂;

R²

is hydrogen, nitro, cyano, trifluoromethyl, carboethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino, alkyl of 1 to 6 carbon atoms, alkylidenemethyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms or halo; with the proviso that either R¹ is selected from a group consisting of alkoxy of 1 to 6 carbon atoms, cycloalkoxy of from 3 to 10 carbon atoms and cyclopentylidenemethyl, and R² is alkoxy of 1 to 6 carbon atoms; or, R³ is phenyl independently substituted at the 3- and 4-positions with alkoxy up to 10 carbon atoms or cycloalkoxy of up to 10 carbon atoms; and,

R³

is (i) phenyl, substituted or unsubstituted with 1 or more substituents each selected independently from a group consisting of nitro, cyano, halo, trifluoromethyl, carboethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, or carbamoyl substituted with alkyl of 1 to 3 carbon atoms, acetoxy, carboxy, hydroxy, amino, amino substituted with an alkyl of 1 to 5 carbon atoms, alkyl of up to 10 carbon atoms, cycloalkyl of up to 10 carbon atoms, alkoxy of up to 10 carbon atoms, cycloalkoxy of up to 10 carbon atoms, alkylidenemethyl up to 10 carbon atoms, cycloalkylidenemethyl of up to 10 carbon atoms, phenyl or methylenedioxy; (ii) pyridine, substituted pyridine, pyrrolidene, imidazole, naphthalene, or thiophene; (iii) cycloalkyl of 4 to 10 carbon atoms, unsubstituted or substituted with one or more substituents each selected independently from the group consisting of nitro, cyano, halo, trifluoromethyl, carboethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino, substituted amino, alkyl of 1 to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms, phenyl;

R⁸

is methyl or R⁹;

R⁹

is alkyl of 2 to 10 carbon atoms, monocycloalkyl of 3 to 10 carbon atoms, polycycloalkyl of up to 10 carbon atoms, benzocycloalkyl of up to 10 carbons atoms;

R¹⁰

together with the carbon atom to which they are attached form a monocycloalkyl group.

[0027] Particularly preferred alkanoic acid derivatives are compounds of the formula III.

wherein:

Y

is -CO(NR⁶)₂, -CO₂H, -CO₂R⁷;

R¹

is R⁹, (CH₂)_nR⁸, OR⁹, CH=CHR⁸, or CH=C(R¹⁰)₂;

R²

is hydrogen, nitro, cyano, trifluoromethyl, carboethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino, alkyl of 1 to 6 carbon atoms, alkylidenemethyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms or halo; with the proviso that either R¹ is selected from a group consisting of alkoxy of 1 to 6 carbon atoms, cycloalkoxy of from 3 to 10 carbon atoms and cyclopentylidenemethyl, and R² is alkoxy of 1 to 6 carbon atoms; or, R³ is phenyl independently substituted at the 3- and 4-positions with alkoxy up to 10 carbon atoms or cycloalkoxy of up to 10 carbon atoms; and,

R³

is (i) phenyl, substituted or unsubstituted with 1 or more substituents each selected independently from a group consisting of nitro, cyano, halo, trifluoromethyl, carboethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, or carbamoyl substituted with alkyl of 1 to carbon atoms, acetoxy, carboxy, hydroxy, amino, amino substituted with an alkyl of 1 to 5 carbon atoms, alkyl of up to 10 carbon atoms, cycloalkyl of up to 10 carbon atoms, alkoxy of up to 10 carbon atoms, cycloalkoxy of up to 10 carbon atoms, alkylidenemethyl up to 10 carbon atoms, cycloalkylidenen of up to 10 carbon atoms, phenyl or methylenedoxy; (ii) pyridine, substituted pyridine, pyrrolidene, imidazole, naphthalene, or thiophene; (iii) cycloalkyl of 4 to 10 carbon atoms, unsubstituted or substituted with one or more substituents each selected independently from the group consisting of nitro, cyano, halo, trifluoromethyl, carboethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino, substituted amino, alkyl of 1 to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms, phenyl;

R⁶

is hydrogen or alkyl of 1 to 6 carbon atoms;

R⁷

is alkyl of 1 to 6 carbon atoms or benzyl;

R⁸

is methyl or R⁹;

R⁹

is alkyl of 2 to 10 carbon atoms, monocycloalkyl of 3 to 10 carbon atoms, polycycloalkyl of up to 10 carbon atoms, benzocycloalkyl of up to 10 carbons atoms;

R¹⁰

together with the carbon atom to which they are attached form a monocycloalkyl or bicycloalkyl group; or,

n

is 1 to 3.

[0028] The term alkyl as used herein denotes a univalent saturated branched or straight hydrocarbon chain. Unless otherwise stated, such chains can contain from 1 to 18 carbon atoms. Representative of such alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, tert-pentyl, hexyl, isohexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, and the like. When qualified by "lower", the alkyl group will contain from 1 to 6 carbon atoms. The same carbon content applies to the parent term "alkane" and to derivative terms such as "alkoxy".

[0029] The term cycloalkyl as used herein denotes a univalent saturated cyclic hydrocarbon chain. Unless otherwise stated, such chains can contain up to 18 carbon atoms. Monocyclicalkyl refers to groups having a single ring group. Polycycloalkyl denotes hydrocarbon systems containing two or more ring systems with two or more ring carbon atoms in common. Benzocycloalkyl signifies a monocyclicalkyl group fused to a benzo group. Representative of monocycloalkyl groups are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, cyclododecyl, cyclotridecyl, cyclotetradecyl, cyclopentadecyl, cyclohexadecyl, cycloheptadecyl, and cyclooctadecyl. Representative of polycycloalkyl include bicyclo[2.2.1] heptyl, bicyclo [3.2.1]octyl, and bicyclo[2.2.2]octyl. Benzocycloalkyl is typified by tetrahydronaphthyl, indanyl, and 1.2-benzocycloheptanyl.

[0030] The compounds can be prepared using methods which are known in general for the preparation of diaryl alkenes. For example, an appropriately substituted bis(aryl) ketone can be treated with a dialkyl cyanomethylphosphonate to yield the corresponding bis aryl acrylonitrile. This can be hydrolysesd to the corresponding carboxylic acid, esters and amides by methods known per se. Alternatively, the substituted bis(aryl) ketone can be treated with an alkyl disubstituted phosphonoacetate or a disubstituted carbamoylmethylphosphonate and lithium hexamethyldisilazide to form the ester or amide, respectively, directly. The substituted bis(aryl) ketone alternatively can be treated with the appropriate triphenylphosphite.

[0031] The bis(aryl) ketones also are obtained by methods known per se such as for example by Friedel-Crafts acylations with acid chlorides in the presence of a Lewis acid.

[0032] Representative examples of these compounds include 3,3-bis-(3,4-dimethoxyphenyl)acrylonitrile, 3,3-bis-(3-ethoxy-4-methoxyphenyl) acrylonitrile, 3-(3-propoxy-4-methoxyphenyl)-3-phenylacrylonitrile, 3-(3-ethoxy-4-methoxyphenyl)-3-phenylacrylonitrile, 3,3-bis-(3-cyclopentoxy-4-methoxyphenyl) acrylonitrile, 3-(3-cyclopentoxy-4-methoxyphenyl)-3-phenylacrylonitrile, 3-(3-cyclopentoxy-4-methoxyphenyl)-3-phenylpropanenitrile, methyl 3-(3-cyclopentoxy-4-methoxyphenyl)-3-phenylpropanoate, 3-(3-ethoxy-4-methoxyphenyl)-3-phenylpropanenitrile, methyl 3-(3-ethoxy-4-methoxyphenyl)-3-phenylpr6panoate, 3,3-bis-(3,4-dimethoxyphenyl) propanenitrile, 3,3-bis-(3-ethoxy-4-methoxyphenyl) propanenitrile, 3-(3,4-dimethoxyphenyl)-3-phenylacrylonitrile,3-(3-ethoxy-4-methoxyphenyl)-3-naphthylpropanenitrile, 3-(3,4-dimethoxyphenyl)-3-phenylpropanenitrile and 3-(3,4-dimethoxyphenyl)-3-(3-ethoxy-4-methoxyphenyl)propanenitrile.

[0033] A further group of preferred compounds include 4-(3-ethoxy-4-methoxyphenyl)-4-(4-pyridyl)butan-2-one; 4-(3-cyclopentoxy-4-methoxyphenyl)-4-(4-pyridyl)butan-2-one; methyl 3-(3-ethoxy-4-methoxyphenyl)-3-(4-pyridyl) propanoate; 3-(3-ethoxy-4-methoxyphenyl)-3-(4-pyridyl)prop-2-enenitrile; 3-(3-ethoxy-4-methoxyphenyl)-3-(4-pyridyl)propanenitrile; 3-(3-cyclopentoxy-4-methoxyphenyl)-3-(4-pyridyl)prop-2-enenitrile; 3-(3-cyclopentoxy-4-methoxyphenyl)-3-(4-pyridyl) propanenitrile; 4,4-bis-(3,4-dimethoxyphenyl)butan-2-one; 4-(3,4-dimethoxyphenyl)-4-(3-ethoxy-4-methoxyphenyl)butan-2-one; 4-(3,4-dimethoxyphenyl)-4-(3-(cyclopentylidenemethyl)-4-methoxyphenyl)butan-2-one; 3-(3,4-dimethoxyphenyl)-3-(3-(cyclopentylidenemethyl)-4-methoxyphenyl)prop-2-enerutrile; 3-(3-(cyclopentylidenemethyl)-4-methoxyphenyl)-3-phenyl-prop-2-enenitrile; 1-(3,4-dimethoxyphenyl)-1-(3-ethoxy-4-methoxyphenyl)pentan-3-one; 1,1-bis-(3,4-dimethoxyphenyl)pentan-3-one; 3-(3,4-dimethoxyphenyl)-3-(3-(cyclopentylidenemethyl)-4-methoxyphenyl)prop-2-enenitrile; 3-(3-(cyclopentylidenemethyl)-4-methoxyphenyl)-3-phenyl-propanenitrile; 3,3-bis-(3-(cycloentylidenemethyl)-4-methoxyphenyl)propanenitrile; 3,3-bis-(3-(cyclopentylidenemethyl)-4-methoxyphenyl)prop-2-enenitrile; 3-(3-(cyclopentylidenemethyl)-4-methoxyphenyl-3-phenyl)propanamide; 3,3-bis-(3-(cyclopentylidenemethyl)-4-methoxyphenyl)propanamide; 3,3-bis-(3-ethoxy-4-methoxyphenyl)propanamide; 3,3-bis-(3,4-dimethoxyphenyl)propanamide; 4-(3,4-dimethoxyphenyl)-4-(4-methoxy-3-exo-norbornyloxyphenyl)but-3-en-2-one; 3-(3,4-dimethoxyphenyl)-3-(4-methoxy-3-exo-norbornyloxyphenyl)prop-2-enenitrile; 3-(3,4-dimethoxyphenyl)-3-(3,4-methylenedioxyphenyl)prop-2-enenitrile; 3-(4-aminophenyl)-3-(3,4-dimethoxyphenyl)prop-2-enenitrile; and 3-(4-aminophenyl)-3-(3-ethoxy-4-dimethoxyphenyl)prop-2-enenitrile.

[0034] These compounds may possess one or more centers of chirality and thus can exist as optical isomers. Both the racemates of these isomers and the individual isomers themselves, as well as diastereoisomers when there are two or more chiral centers, are within the scope of the present invention. The racemates can be used as such or can be separated into their individual isomers mechanically as by chromatography using a chiral absorbent. Alternatively, the individual isomers can be prepared in chiral form or separated chemically from a mixture by forming salts with a chiral acid, such as the individual enantiomers of 10-camphorsulfonic acid, camphoric acid, alpha-bromocamphoric acid, methoxyacetic acid, tartaric acid, diacetyltartaric acid, malic acid, pyrrolidone-5-carboxylic acid, and the like, and then freeing one or both of the resolved bases, optionally repeating the process, so as to obtain either or both isomers substantially free of the other; i.e., in a form having an optical purity of >95%. In addition, the compounds in which R⁴ and R⁵ taken together are a carbon-carbon bond can exist as cis (Z) and trans (E) isomers.

[0035] The compounds can be used, under the supervision of qualified professionals, to inhibit the undesirable effects of TNFα, NFκB, and phosphodiesterase. The compounds can be administered orally, rectally, or parenterally, alone or in combination with other therapeutic agents including antibiotics, steroids, etc., to a mammal in need of treatment. Oral dosage forms include tablets, capsules, dragees, and similar shaped, compressed pharmaceutical forms. Isotonic saline solutions containing 20-100 milligrams/milliliter can be used for parenteral administration which includes intramuscular, intrathecal, intravenous and intra-arterial routes of administration. Rectal administration can be effected through the use of suppositories formulated from conventional carriers such as cocoa butter.

[0036] Dosage regimens must be titrated to the particular indication, the age, weight, and general physical condition of the patient, and the response desired but generally doses will be from about 1 to about 1000 milligrams/day as needed in single or multiple daily administration. In general, an initial treatment regimen can be copied from that known to be effective in interfering with TNFα activity for other TNFα mediated disease states by the compounds of the present invention. Treated individuals will be regularly checked for T cell numbers and T4/T8 ratios and/or measures of viremia such as levels of reverse transcriptase or viral proteins, and/or for progression of cytokine-mediated disease associated problems such as cachexia or muscle degeneration. If no effect is observed following the normal treatment regimen, then the amount of cytokine activity interfering agent administered is increased, e.g., by fifty percent a week.

[0037] The compounds of the present invention can also be used topically in the treatment or prophylaxis of topical disease states mediated or exacerbated by excessive TNFα production, such as viral infections, for example those caused by the herpes viruses or viral conjunctivitis, psoriasis, other skin disorders and diseases, etc.

[0038] The compounds can also be used in the veterinary treatment of mammals other than humans in need of prevention or inhibition of TNFα production. TNFα mediated diseases for treatment, therapeutically or prophylactically, in animals include disease states such as those noted above, but in particular viral infections. Examples include feline immunodeficiency virus, equine infectious anaemia virus, caprine arthritis virus, visna virus, and maedi virus, as well as other lentiviruses.

[0039] Inhibition of PDE III, PDE IV, TNFα and NFκB by these compounds can be conveniently assayed using methods known in the art, e.g., enzyme immunoassay, radioimmunoassay, immunoelectrophoresis, affinity labeling, etc., of which the following are typical.

Enzyme-linked Immunosorbent Assay for TNFα

[0040] PBMC isolation: PBMC from normal donors were obtained by Ficoll-Hypaque density centrifugation. Cells were cultured in RPMI supplemented with 10% AB+ serum, 2mM L-glutamine, 100 U/mL penicillin and 100 mg/mL streptomycin.

[0041] PBMC suspensions: Drugs were dissolved in dimethylsulfoxide (Sigma Chemical), further dilutions were done in supplemented RPMI. The final dimethylsulfoxide concentration in the presence or absence of drug in the PBMC suspensions was 0.25 wt %. Drugs were assayed at half-log dilutions starting at 50 mg/mL. Drugs were added to PBMC (10⁶ cells/mL) in 96 wells plates one hour before the addition of LPS.

[0042] Cell stimulation: PBMC (10⁶ cells/mL) in the presence or absence of drug were stimulated by treatment with 1 mg/mL of LPS from Salmonella minnesota R595 (List Biological Labs, Campbell, CA). Cells were then incubated at 37°C for 18-20 hours. Supernatants were then harvested and assayed immediately for TNFα levels or kept frozen at -70°C (for not more than 4 days) until assayed.

[0043] TNFα Determination: The concentration of TNFα in the supernatant was determined by human TNFα ELISA kits (ENDOGEN, Boston, MA) according to the manufacturer's directions.

[0044] Phosphodiesterase can be determined in conventional models. For example, using the method of Hill and Mitchell, U937 cells of the human promonocytic cell line are grown to 1x10⁶ cells /mL and collected by centrifugation. A cell pellet of 1x10⁹ cells is washed in phosphate buffered saline and then frozen at -70°C for later purification or immediately lysed in cold homogenization buffer (20mM Tris-HCI, pH 7.1, 3 mM 2-mercaptoethanol, 1 mM magnesium chloride, 0.1 mM ethylene glycol-bis-(β-aminoethyl ether)-N,N,N',N'-tetraacetic acid (EGTA), 1 µM phenylmethylsulfonyl fluoride (PMSF), and 1 µg/mL leupeptin). Cells are homogenized with 20 strokes in a Dounce homogenizer and supernatant containing the cytosolic fraction are obtained by centrifugation. The supernatant then is loaded onto a Sephacryl S-200 column equilibrated in homogenization buffer. Phosphodiesterase is eluted in homogenization buffer at a rate of approximately 0.5 mL/min and fractions are assayed for phosphodiesterase activity -/+ rolipram. Fractions containing phosphodiesterase activity( rolipram sensitive) are pooled and aliquoted for later use.

[0045] The phosphodiesterase assay is carried out based on procedure described by Hill and Mitchell. The assay is carried out in a total volume of 100 µl containing various concentration of test compounds, 50mM Tris-HCI, pH 7.5,5 mM magnesium chloride and 1 µM cAMP of which 1% was ³H cAMP. Reactions are incubated at 30°C for 30 minutes and terminated by boiling for 2 minutes. The amount of phosphodiesterase IV containing extract used for these experiments is predetermined such that reactions are within the linear range and consumed less than 15% of the total substrate. Following termination of reaction, samples are chilled at 4°C and then treated with 10µl 10 mg/mL snake venom for 15 min at 30°C. Unused substrate then is removed by adding 200µl of a quaternary ammonium ion exchange resin (AG1-X8, BioRad) for 15 minutes. Samples then are spun at 3000 rpm, 5 min and 50 µl of the aqueous phase are taken for counting. Each data point is carried out in duplicate and activity is expressed as percentage of control. The IC₅₀ of the compound then is determined from dose response curves of a minimum of three independent experiments.

[0046] The following examples will serve to further typify the nature of this invention but should not be construed as a limitation in the scope thereof, which scope is defined solely by the appended claims.

EXAMPLE 1

3,3-bis-(3,4-Dimethoxyphenyl)acrylonitrile

A. 3,4,3',4,'-Tetramethoxybenzophenone

[0047] To a stirred ice bath cooled solution of veratole (2.07 g, 15.0 mmol) in 30 mL of methylene chloride under nitrogen was added aluminum chloride (2.20 g, 16.5 mmol). A slight exotherm resulted. To the reaction mixture was then added 3,4-dimethoxybenzoyl chloride (3.01 g, 15.0 mmol) and 20 mL of methylene chloride. The reaction was then allowed to warm to room temperature and then refluxed for 3.5 hours and then allowed to stir at room temperature for 16 hours. The reaction mixture was then poured into 50 mL of ice water and stirred for 15 minutes. This mixture was extracted with methylene chloride (2 x 25 mL each). The combined extracts were dried over sodium sulfate and concentrated in vacuo to afford the crude product as a tan solid. The crude product was purified by flash chromatography (silica gel, 4/96 ethyl acetate/methylene chloride) to afford 2.97 g (66%) of the product as a white powder: ¹H NMR (CDCl₃) δ 7.4 (m, 4 H), 6.91 (m, 2 H), 3.97 (s, 6 H), 3.95 (s, 6 H); ¹³C NMR (DMSO-d₆) δ 194.4, 152.5, 148.8, 130.7, 124.7, 112.2, 109.7, 56.0. Anal. Calcd for C₁₇H₁₈O₅. Theoretical: C, 67.54; H, 6.00. Found: C, 67.42; H, 6.03.

B. 3,3-bis-(3',4'-Dimethoxyphenyl)acrylonitrile

[0048] To an ice bath cooled stirred suspension of sodium hydride (5.0 mmol) in 20 mL of tetrahydrofuran was added 0.8 mL of diethyl cyanomethylphosphonate dropwise via syringe. The mixture was allowed to warm to room temperature and then 3,4,3',4,'-tetramethoxybenzophenone (1.51 g, 5.00 mmol) and 10 mL of tetrahydrofuran were added. The mixture was stirred for 5 days and then quenched with 100 mL of H₂O. The reaction mixture was then extracted with methylene chloride (50 mL and 25 mL). The combined extracts were dried over sodium sulfate and concentrated to afford the crude product as an oil. The crude product was purified by flash chromatography to afford the product as a white wax: ¹H NMR (CDCl₃) δ 7.95 (br m, 6 H), 5.57 (s, 1 H), 3.94 (s, 3 H), 3.92 (s, 3 H), 3.87 (s, 3 H), 3.84 (s, 3 H); ¹³C NMR (DMSO-d₆) δ 162.4, 151.0, 150.5, 148.8, 148.5, 131.8, 129.5, 123.2, 122.2, 118,6, 112.7, 111.4, 110.7, 110.7, 91.9, 56.0, 55.9, 55.9.

EXAMPLE 2

cis and trans 3-(3,4-Dimethoxyphenyl)-3-(3-ethoxy-4-methoxyphenyl)acrylonitrile

A. 3, 4-Dimethoxy-3-ethoxy-4-methoxybenzophenone

[0049] To an ice bath cooled stirred suspension of 3-ethoxy-4-methoxybenzoic acid (0.98 g, 5.0 mmol) in 20 mLmethylene chloride was added oxalyl chloride (0.44 mL, 5.0 mmol) and 2 drops of N,N dimethylformamide (dimethylformamide). The resulting yellow mixture was stirred at room temperature for 35 minutes at which time a solution had formed. The solution was cooled in an ice bath and veratrole (0.64 mL, 5.0 mmol) was added followed by aluminum chloride (0.73 g, 5.5 mmol). The ice bath was removed and the mixture was stirred at room temperature. The reaction was monitored by HPLC (Waters Nova-Pak/C,8 column 3.9 x 150 mm, 4 micron, 1mL/min, 35/65 acrylonitrile/0.1% aqueous phosphoric acid and after 37 hours the reaction was complete. The reaction mixture was poured into 30 mL of ice, stirred for 30 minutes and was then extracted with methylene chloride (3 x 20 mL). The methylene chloride extracts were washed successively with aqueous sodium bicarbonate (30 mL), water (2 x 50 mL) and brine (50 nlL). The organic layer was then dried over magnesium sulfate, filtered and concentrated in vacuo to afford 1.05 g of a brown solid. The crude product was purified by flash column chromatography (silica gel, 5% ethyl acetate/methylene chloride) and the resulting product was then dried in vacuo (60 °C, < 1mmHg) to afford 0. 8 g (51%) of the product: mp 122-124.5 °C; ¹H NMR (CDCl3) δ 7.48-7.34 (m, 4 H),6.98-6.86 (m, 2 H), 4.16 (q, J = 7 Hz, 2 H), 3.96 (s, 3 H), 3.96 (s, 3 H), 3.94 (s, 3 H),1.49 (t, J = 7 Hz, 3 H); ¹³C NMR (CDCl3) δ 194.4, 152.8, 152.5, 148.8, 148.0, 130.7, 130.6, 124.6, 124.5, 113.5, 112.2, 109.9, 109.7, 64.3, 55.9, 55.9, 14.6; HPLC (Waters Nova-Pak/C,8 column, 3.9 x 150 mm, 4 micron, 1 mL/min, 35/65 acrylonitrile/0.1% aqueous phosphoric acid 8 min, 99%; Anal. Calcd for C₁₈H₂₀O₅. Theoretical: C, 68.34; H, 6.37. Found: C, 68.56; H, 6.51.

B. cis and trans 3-(3, 4-Dimethoxyphenyl)-3-(3-ethoxy-4-methoxyphenyl)acrylonitrile

[0050] To an ice bath cooled stirred solution of diethylcyanomethylphosphonate (0.9 mL, 5.5 mmol) in 15 mL of tetrahydrofuran was added a 1.3 M solution of lithium hexamethyldisilazide (4.2 niL, 5.5 mmol) in tetrahydrofuran. The solution was allowed to warm to room temperature and was stirred for 30 minutes and then a slurry of 3, 4-dimethoxy-3-ethoxy-4-methoxybenzophenone (1.58 g, 5.00 mmol) in 20 mL of tetrahydrofuran was added. The reaction mixture was stirred at room temperature for 21 hours and was then quenched with I 00 mL of water. The resulting mixture was extracted with methylene chloride (2 x 50 mL). The combined extracts were washed with water, chied over magnesium sulfate, and concentrated in vacuo to afford the crude product as an orange oil. The crude product was purified by flash column chromatography (silica gel, 3% ethyl acetate/methylene chloride) and then recrystallized from hexane/ethyl. The resulting product was then dried in vacuo (40 °C, < I mmHg) to afford 0.6 g (35 %) of a white solid: mp 103-106 °C; ¹H NMR (CDCl₃) δ 7.10-6.75 (m, 6 H), 5.55 (s, 1H), 4.17-3.76 (m, I 1 H), 1.54-1.36 (m, 3 H); ¹³C NMR (CDCl₃) δ 162.5, 151.0, 150.8, 150.5, 148.8, 148.6, 148.1, 147.8, 131.9, 131.7, 129.6, 129.5, 123.2, 123.1, 122.1, 122.0, 118.6, 114.2, 1 1 2.9, 112.8, 111.4, 110.9, 110.9, 110.7, 110.7, 91.8, 64.5, 56.0, 5 5.9, 14.6; HPLC (Waters Nova-Pak/C,8 column, 3.9 x 150 mm, 4 micron, 1 mL/min, 45/55 acrylonitrile/0.1% aqueous phosphoric acid 7 min, 100%; Anal. Calcd for C₂₀H₂₁NO₄. Theoretical: C, 70.78; H, 6.24; N, 4.13. Found: C, 70.62; H, 6.2 1; N, 4.07.

EXAMPLE 3

3-(3,4-Dimethoxyphenyl)-3-phenylacetate

A. 3,4-Dimethoxybenzophenone

[0051] 3,4-Dimethoxybenzophenone was prepared analogously to 3,4,3',4'-tetramethoxybenzophenone using veratrole (2 mL, 15 mmol), aluminum chloride (2.2 g, 16.5 mmol) and benzoyl chloride (1.8 mL, 15.5 mmol). The crude mixture was purified by flash column chromatography (silica gel, 3% ethyl acetate/methylene chloride) to yield 3.44 g (93%) of the product as a white solid: mp 99-100 °C; ¹H NMR (CDCl₃) δ 7.82-7.30 (m, 7 H), 6.95-6.85 (m, 1 H), 3.96 (s, 3 H), 3.94 (s, 3 H); ¹³C NMR (CDCl₃) δ 195.5, 153.0, 149.0, 138.2, 131.8, 130.2, 129.6, 128.1, 125.4, 112.1, 109.7, 56.0, 56.0; Anal. Calcd for C₁₅H₁₄O₃. Theoretical: C, 74.36; H, 5.82. Found: C, 74.21; H, 6.01.

B. 3-(3,4-Dimethoxyphenyl)-3-phenylacetate (E and Z Isomers)

[0052] 3-(3,4-Dimethoxyphenyl)-3-phenylacetate was prepared analogously to 3,3-bis-(3,4-dimethoxyphenyl)acrylate using 3,4-dimethoxybenzophenone (4.8 g, 20 mmol), trimethylphosphonoacetate (4.1 g, 22 mmol) and lithium hexamethyldisilazide (22 mL, 22 mmol, 1M) with a reaction time of 138 hours at reflux. The crude mixture was purified by flash column chromatography (silica gel, 1% ethyl acetate/methylene chloride) to afford 14.39 g (73%) of a mixture of the E and Z isomers as an oil. The isomers were separated by additional purification (silica gel, 1% ethyl acetate/methylene chloride) to afford pure samples of each of the isomers.

[0053] Isomer 1: ¹H NMR (CDCl₃) δ 7.40-7.36 (m, 3 H), 7.26-7.20 (m, 2 H), 6.88 (s, 1 H), 6.80 (s, 2 H), 6.30 (s, 1 H), 3.88 (s, 3 H), 3.82 (s, 3 H), 3.60 (s, 3 H); ¹³C NMR (CDCl₃) δ 166.5, 156.9, 150.4, 148.7, 138.9, 133.4, 129.1, 128.1, 128.0, 127.8, 122.1, 114.9; 110.8, 110.6, 55.9, 55.8, 51.1; Anal. Calcd for C₁₈H₁₈O₄. Theoretical: C, 72.47; H, 6.08. Found: C, 72.08; H, 6.11.

[0054] Isomer 2: ¹H NMR (CDCl₃) δ 7.35-7.32 (m, 5 H), 6.90-6.83. (m, 2 H), 6.73 (s, 1 H), 6.30 (s, 1 H), 3.92 (s, 3 H), 3.81 (s, 3 H), 3.64 (s, 3 H); ¹³C NMR (CDCl₃) δ 166.6, 156.7, 149.2, 148.3, 141.2, 131.1, 129.4, 128.5, 128.3, 122.4, 116.4, 112.7, 110.4, 55.8, 55.7, 51.2; Anal. Calcd for C₁₈H₁₈O₄. Theoretical: C, 72.47; H, 6.08. Found: C, 72.28; H, 5.94.

EXAMPLE 4

3-(3-Ethoxy-4-methoxyphenyl)-3-phenylacrylonitrile (E and Z Isomers)

[0055] 3-(3-Ethoxy-4-methoxyphenyl)-3-phenylacrylonitrile was prepared analogously to 3,3-bis-(3,4-dimethoxyphenyl)acrylate using 3-ethoxy-4-methoxybenzophenone (1.3g, 5mmol), diethylcyanomethylphosphonate (0.9mL, 5.5mmol) and lithium hexamethyldisilazide (4.2mL, 5.5mmol, 1.3M) with a reaction time of 24 hours at room temperature. The crude mixture was purified by flash column chromatography (silica gel, methylene chloride) to afford 1.35g (96%) of a mixture of the E and Z isomers as a white solid: mp 74-77°C; ¹H NMR (CDCl₃) δ 7.50-7.24 (m, 10 H), 7.07-6.75 (m, 6 H), 5.67 (s, 1 H), 5.60 (s, 1 H), 4.15-3.95 (m, 4 H), 3.92 (s, 3 H), 3.89 (s, 3 H), 1.50-1.36 (m, 6 H); ¹³C NMR (CDCl₃) δ 162.8, 162.7, 151.4, 150.9, 148.1, 147.1, 147.9, 139.3, 137.1, 131.3, 130.2, 129.9, 129.5, 129.3, 128.6, 128.5, 128.4, 123.1, 122.0, 118.3, 118,2, 113.9, 112.5, 110.9, 93.3, 92.9, 64.4, 55.9, 55.9, 14.6; Anal. Calcd for C₁₈H₁₇NO₂. Theoretical: C, 77.40; H, 6.13; N, 5.01. Found: C, 77.14; H, 6.06; N, 4.75.

EXAMPLE 5

3-(3-Ethoxy-4-methoxyphenyl)-3-phenylpropionitrile

[0056] To a solution of 3-(3-ethoxy-4-methoxyphenyl)-3-phenylacrylonitrile (0.9g, 3.2 mmol) in a mixture of ethanol and ethyl acetate (20 mL/ 30mL) was added 0.5 g of 10% palladium on carbon catalyst in portions. The mixture was hydrogenated in a Parr-Shaker apparatus at 55-60 psi of hydrogen for 12 days. The reaction mixture was filtered through celite and the filtrate was concentrated in vacuo to afford the crude product. The crude product was purified by flash column chromatography (silica gel, 4% hexane/methylene chloride) to afford 0.15g (15%) of the product as an oil: ¹H NMR (CDCl₃) δ 7.40-7.16 (m, 5 H); 6.88-6.78 (m, 3 H), 4.32 (t, J = 7.5 Hz, 1 H), 4.03 (q, J = 7 Hz, 2 H), 3.85 (s, 3 H), 3.00 (d, J = 7.5 Hz, 2 H), 1.42 (t, J = 7 Hz, 3 H); ¹³C NMR (CDCl₃) δ 148.7, 148.5, 141.5, 133.7, 128.8, 127.4, 127.3, 119.5, 118.5, 112.7, 111.6, 64.4, 55.9, 46.7, 24.5, 14.7; Anal. Calcd for C₁₈H₁₇NO₂. Theoretical: C, 76.84; H, 6.81; N,.4.98. Found: C, 76.53; H, 6.92; N, 4.95.

EXAMPLE 6

3-(3,4-Dimethoxyphenyl)-3-(3',5)-dimethoxyphenyl)-acrylonitrile (E and Z Isomers)

A. 3,4,3',5'-Tetramethoxybenzophenone

[0057] 3,4,3',5'-Tetramethoxybenzophenone was prepared analogously to 4-(3,4-dimethoxybenzoyl)pyridine using butyl lithium (9 mL, 22 mmol, 2.5M), 4-bromoveratrole (2.9 mL, 20 mmol) and 3,5-dimethoxybenzonitrile (3.75 g, 23 mmol). The crude product was purified by flash column chromatography (silica gel, methylene chloride) to afford 1.54 g (26%) of the product: mp 107-110 °C; ¹H NMR (CDCl₃) δ 7.53-7.39 (m, 2 H), 6.95-6.84 (m, 3 H), 6.70-6.60 (m, 1 H), 3.96 (s, 3 H), 3.95 (s, 3 H), 3.83 (s, 6 H); ¹³C NMR (CDCl₃) δ 195.0, 160.4, 153.0, 148.9, 140.1, 130.0, 125.4, 112.0, 109.7, 107.5, 104.1, 56.0, 55.5; Anal. Calcd for C₁₇H₁₈O₅. Theoretical: C, 67.54; H, 6.00. Found: C, 67.38; H, 5.96.

B. 3-(3,4-Dimethoxyphenyl)-3-(3',5'-dimethoxyphenyl)acrylonitrile

[0058] 3-(3,4-Dimethoxyphenyl)-3-(3',5'-dimethoxyphenyl)acrylonitrile was prepared analogously to methyl 3,3-bis-(3,4-dimethoxyphenyl)acrylate using 3,4,3',5'-tetramethoxybenzophenone (0.7 g, 2.3 mmol), diethylcyanomethylphosphonate (0.42 mL, 2.5 mmol) and lithium hexamethyldisilazide (1.9 mL, 2.5 mmol, 1.3M) with a reaction time of 60 hours at room temperature. The crude product was purified by flash chromatography (silica gel, 1% ethyl acetate/methylene chloride) to afford 0.66 g (81%) of a mixture of the E and Z isomers as a white solid: mp 88-90°C; ¹H NMR (CDCl₃) δ 7.10-6.80 (m, 6 H), 6.61-6.40 (m, 6 H), 5.66 (s, 1 H), 5.61 (s, 1 H), 3.94 (s, 3 H), 3.91 (s, 3 H), 3.87 (s, 3 H), 3.84 (s, 3 H), 3.80 (s, 3 H), 3.77 (s, 6 H); ¹³C NMR (CDCl₃) δ 162.7, 162.5, 160.7, 160.6, 151.1, 150.6, 148.8, 148.5, 141.3, 138.9, 131.1, 129.2, 123.2, 122.1, 118.2, 118.0, 112.6, 110.9, 110.7, 110.7, 107.6, 107.0, 102.1, 102.0, 93.4, 93.1, 56.0, 55.9, 55.5, 55.4; Anal. Calcd for C₁₉H₁₉NO₄. Theoretical: C, 70.14; H, 5.89; N, 4.30. Found: C, 70.33; H, 5.89; N, 4.03.

EXAMPLE 7

3-(3,4-Dimethoxyphenyl)-3-(3'-nitrophenyl)acrylonitrile

A. 3,4-Dimethoxy-3'-nitrobenzophenone

[0059] To a stirred ice bath cooled solution of veratrole (2.55 mL, 20 mmol) in methylene chloride (30 mL) under nitrogen was added aluminum chloride (2.93 g, 22 mmol). A slight exotherm resulted. To the resulting mixture was added 3-nitrobenzoyl chloride (3.8 g, 20 mmol) in 30 mL of methylene chloride. The reaction was then allowed to warm to room temperature and followed by heating to refluxed. After 5 hours at reflux the reaction mixture was allowed to cool to room temperature and stirred for 72 hours. The reaction mixture was then poured into 100 mL of iced water and stirred for 20 minutes. This mixture was extracted with CH₂Cl₂ (3 x 60 mL). The organic layer was dried over magnesium sulfate and concentrated in vacuo to afford the crude product as a green solid. The crude product was purified by flash column chromatography (silica gel, CH₂Cl₂) to afford 2.21 g (39%) of the product as a yellow solid: mp 133-135°C; ¹H NMR (CDCl₃) δ 8.64-8.56 (m, 1 H), 8.49-8.39 (m, 1 H), 8.10-8.05 (m, 1 H), 7.76-7.65 (m, 1H), 7.55-7.47 (m, 1 H), 7.36-7.29 (m, 1 H), 7.00-6.87 (m, 1 H), 3.99 (s, 3 H), 3.97 (s, 3 H); ¹³C NMR (CDCl₃) δ 192.8, 153.8, 149.4, 147.9, 139.7, 135.2, 129.5, 128.9, 126.2, 125.6, 124.4, 11.8, 110.0, 56.2, 56.1; Anal. Calcd for C₁₅H₁₃NO₅. Theoretical: C, 62.72; H, 4.56; N, 4.88. Found: C, 62.74; H, 4.59; N, 4.89.

B. 3-(3,4-Dimethoxyphenyl)-3-(3'-nitrophenyl)acrylonitrile

[0060] 3-(3,4-Dimethoxyphenyl)-3-(3'-nitrophenyl)acrylonitrile was prepared analogously to methyl 3,3-bis-(3,4-dimethoxyphenyl)acrylate using 3,4-dimethoxy-3'nitrobenzophenone (1.44 g, 5 mmol), diethylcyanomethylphosphonate (0.91 mL, 5.5 mmol) and lithium hexamethyldisilazide (4.2 mL, 5.5 mmol, 1.3M) with a reaction time of 24 hours at room temperature. The crude product was purified by flash chromatography (silica gel, 3% hexane/methylene chloride) to afford 1.12 g (72%) of a mixture of the E and Z isomers as a yellow solid: mp 117.5-120 °C; ¹H NMR (CDCl₃) δ 8.40-8.17 (m, 4 H), 7.90-7.55 (m, 4 H), 7.08-6.89 (m, 6 H), 5.84 (s, 1 H), 5.71 (s, 1 H), 3.95 (s, 3 H), 3.92 (s, 3 H), 3.88 (s, 3 H), 3.85 (s, 3 H); ¹³CNMR (CDCl₃) δ 160.2, 160.1, 151.7, 151.1, 149.2, 148.3, 148.2, 141.0, 138.8, 135.4, 134.4, 129.9, 129.7, 129.7, 128.1, 124.8, 124.6, 124.4, 123.3, 123.1, 122.3, 117.4, 117.3, 112.3, 111.0, 110.4, 95.7, 94.8, 56.0, 55.9; Anal. Calcd for C₁₇H₁₄N₂O₄. Theoretical: C, 65.80; H, 4.55; N, 9.03. Found: C, 65.57; H, 4.64; N, 8.92.

EXAMPLE 8

3-(3'-Aminophenyl)-3-(3,4-dimethoxyphenyl)acrylonitrile (E and Z Isomers)

[0061] To a solution of 3-(3,4-dimethoxyphenyl)-3-(3'-nitrophenyl)acrylonitrile (0.7 g, 2.3 mmol) in 40 mL of ethyl acetate was added 0.1 g of 10% palladium on carbon catalyst. The mixture was hydrogenated in a Parr-Shaker apparatus at 55-60 psi of hydrogen for 2.5 hours. The reaction mixture was filtered through celite and the filtrate was concentrated in vacuo to afford the crude product. The crude product was purified by flash column chromatography (silica gel, 15% ethyl acetate/methylene chloride) to afford 0.25 g (56%) of a mixture of the E and Z isomers as a yellow solid: mp 100-101 °C; ¹H NMR (CDCl₃) δ 7.30-6.59 (m, 14 H); 5.63 (s, 1 H), 5.59 (s, 1 H), 3.94 (s, 3 H), 3.91 (s, 3 H), 3.87 (s, 3 H), 3.84 (s, 3 H); ¹³C NMR (CDCl₃) δ 163.1, 162.9, 151.1, 150.5, 148.8, 148.7, 146.5, 146.4, 140.4, 138.2, 131.5, 129.5, 129.5, 129.4, 123.2, 122.1, 119.9, 119.0, 118.4, 118.2, 116.8, 116.6, 115.9, 115.0, 112.7, 111.0, 110.7, 93.3, 92.7, 56.1, 56.0, 55.9; Anal. Calcd for C₁₇H₁₆N₂O₃. Theoretical: C, 72.84; H, 5.75; N, 9.99. Found: C, 72.48; H, 6.05; N, 9.58.

EXAMPLE 9

3,4-Dimethoxy-3'-aminobenzophenone

[0062] To a solution of 3,4-dimethoxy-3'-nitrobenzophenone (0.5 g, 1.7 mmol) in 40 mL of ethyl acetate was added 0.05 g of 10% palladium on carbon catalyst. The mixture was hydrogenated in a Parr-Shaker apparatus at 55-60 psi of hydrogen for 1.5 hours. The reaction mixture was filtered through celite and the filtrate was concentrated in vacuo to afford the crude product. The crude product was purified by flash column chromatography (silica gel, 10% ethyl acetate/methylene chloride) to afford 0.17 g (38%) of the product as a yellow solid: mp 157-175 °C; ¹H NMR (CDCl₃) δ 7.56-6.80 (m, 7 H); 3.95 (s, 3 H), 3.94 (s, 3 H); ¹³C NMR (CDCl₃) δ 195.7, 152.9, 148.9, 146.4, 139.3, 130.3, 128.9, 125.4, 120.1, 118.4, 115.6, 112.1, 109.7, 56.0, 56.0; Anal. Calcd for C₁₅H₁₅NO₃. Theoretical: C, 70.02; H, 5.88; N, 5.44. Found: C, 70.00; H, 6.10; N, 5.13.

EXAMPLE 10

3-(3,4-Dimethoxyphenyl)-3-(4-nitrophenyl)acrylonitrile (E and Z Isomers)

A. 3,4-Dimethoxy-4'-nitrobenzophenone

[0063] 3,4-Dimethoxy-4'-nitrobenzophenone was prepared analogously to 3,4-dimethoxy-3'-nitrobenzophenone using veratrole (3.8 mL, 30 mmol), aluminum chloride (4.4 g, 33 mmol) and 4-nitrobenzoyl chloride (5.7 g, 30 mmol) with a reaction time of 48 hours at reflux. The crude mixture was purified by flash column chromatography (silica gel, 4% ethyl acetate/methylene chloride) to afford 1.69 g (78%) of the product as a white solid: mp 172-173 °C; ¹H NMR (CDCl₃) δ 8.43-8.31 (m, 2 H), 7.97-7.86 (m, 2 H), 7.55-7.46 (m, 1 H), 7.40-7.30 (m, 1 H), 7.00-6.89 (m, 1 H), 3.99 (s, 3 H), 3.96 (s, 3 H); ¹³C NMR (CDCl₃) δ 193.4, 153.8,149.4, 149.3, 143.8, 130.2, 130.0, 125.8, 123.4, 111.7, 109.9, 56.1, 56.0; Anal. Calcd for C₁₅H₁₃NO₅. Theoretical: C, 62.72; H, 4.56; N, 4.88. Found: C, 62.49; H, 4.68; N, 4.86.

B. 3-(3,4-Dimethoxyphenyl)-3-(4'-nitrophenyl)acrylonitrile

[0064] 3-(3,4-Dimethoxyphenyl)-3-(4'-nitrophenyl)acrylonitrile was prepared analogously to methyl 3,3-bis-(3',4'-dimethoxyphenyl)acrylate using 3,4-dimethoxy-4'nitrobenzophenone (4 g, 14 mmol), diethylcyanomethylphosphonate (2.5 mL, 15.4 mmol) and lithium hexamethyldisilazide (11.8 mL, 15.4 mmol, 1.3M) with a reaction time of 17 hours at room temperature. The crude product was purified by chromatography (silica gel, 3% hexane/methylene chloride) to afford 2.38 g (55%) of a mixture of the E and Z isomers as a yellow solid: mp 117.5-120 °C; ¹H NMR (CDCl₃) δ 8.40-8.20 (m, 4 H), 7.70-7.46 (m, 4 H), 7.06-6.75 (m, 6 H), 5.84 (s, 1 H), 5.70 (s, 1 H), 3.95 (s, 3 H), 3.93 (s, 3 H), 3.88 (s, 3 H), 3.85 (s, 3 H); ¹³C NMR (CDCl₃) δ 160.3, 151.7, 151.1, 149.2, 148.9, 148.7, 148.5, 148.5, 143.5, 130.6, 129.9, 129.6, 128.2, 123.7, 123.1, 122:2, 117.4, 117.3, 112.3, 111.0, 110.5, 96.2, 94.9, 56.0, 56.0; Anal. Calcd for C₁₇H₁₄N₂O₄. Theoretical: C, 65.80; H, 4.55; N, 9.03. Found: C, 65.45; H, 4.66; N, 8.82.

EXAMPLE 11

3-(4-Aminophenyl)-3-(3,4-dimethoxyphenyl)acrylonitrile

[0065] 3-(4-Aminophenyl)-3-(3,4-dimethoxyphenyl)acrylonitrile was prepared analogously to 3-(3,4-dimethoxyphenyl)-3-(3-aminophenyl)acrylonitrile using 3-(3,4-dimethoxyphenyl)-3-(4-nitrophenyl)acrylonitrile (1.24 g, 4 mmol) and 0.15 g of 10% palladium on carbon catalyst in 100 mL of ethyl acetate. The crude mixture was purified by flash column chromatography (silica gel, 5% ethyl acetate/methylene chloride) to afford 0.19 g (17%) of a mixture of the E and Z isomers as a yellow solid: mp 150-152 °C; ¹H NMR (CDCl₃) δ 7.38-6.56 (m, 14 H); 5.51 (s, 1 H), 5.44 (s, 1 H), 3.97 (br s, 4 H), 3.93 (s, 3 H), 3.91 (s, 3 H), 3.85 (s, 3 H), 3.82 (s, 3 H); ¹³C NMR (CDCl₃) δ 162.8, 162.6, 150.8, 150.3, 148.8, 148.7, 148.5, 148.4, 132.4, 131.4, 130.1, 129.5, 129.9, 128.6, 126.7, 123.0, 122.1, 114.4, 114.3, 112.8, 111.6, 110.7, 90.3, 89.9, 56.0, 55.9; Anal. Calcd for C₁₇H₁₆N₂O₃. Theoretical: C, 72.84; H, 5.75; N, 9.99. Found: C, 72.79; H, 5.83; N, 9.59.

EXAMPLE 12

3-(3,4-Dimethoxyphenyl)-3-(4-methylphenyl)acrylonitrile

A. 3,4-Dimethoxy-4'-methylbenzophenone

[0066] The title compound was prepared analogously to 3,4,3',4'-tetramethoxybenzophenone using veratrole (3.9 mL, 28 mmol), aluminum chloride (4.1 g, 31 mmol) and 4-methyl-benzoyl chloride (4.6 mL, 29 mmol) with a reaction time of 6 hours at room temperature. The crude mixture was purified by flash column chromatography (silica gel, 2% ethyl acetate/methylene chloride) to afford 4.22 g (59%) of the product as a white solid: mp 121.5-122 °C; ¹H NMR (CDCl₃) δ 7.70-7.67 (d, J = 8 Hz, 2 H), 7.48-7.26 (m, 4 H), 6.91-6.88 (d, J = 8.3 Hz, 1 H), 6.96 (s, 3 H), 3.94 (s, 3 H), 2.44 (s, 3 H); ¹³C NMR (CDCl₃)δ 195.1, 152.6, 148.8, 142.4, 135.3, 130.3, 129.8, 128.7, 125.0, 112.0, 109.6, 55.9, 55.8, 21.4; Anal. Calcd for C₁₆H₁₆O₃. Theoretical: C, 74.98; H, 6.29. Found: C, 74.84; H, 6.43.

B. 3-(3,4-Dimethoxyphenyl)-3-(4-methylphenyl)acrylonitrile

[0067] 3-(3,4-Dimethoxyphenyl)-3-(4-methylphenyl)acrylonitrile was prepared analogously to methyl 3,3-bis-(3,4-dimethoxyphenyl)acrylate using 3,4-dimethoxy-4'-methylbenzophenone (2.3 g, 9 mmol), diethylcyanomethylphosphonate (1.8 mL, 9.9 mmol) and lithium hexamethyldisilazide (10 mL, 9.9 mmol, 1M) with a reaction time of 22 hours at room temperature. The crude product was purified by chromatography (silica gel, 1% ethyl acetate/methylene chloride) to afford 1.83 g (73%) of a mixture of the E and Z isomers as a white solid: mp 83.5-86.5 °C; ¹H NMR (CDCl₃) δ 7.35-7.20 (m, 8 H), 7.04-6.81 (m, 6 H), 5.62 (s, 1 H), 5.59 (s, 1 H), 3.90 (s, 3 H), 3.90 (s, 3 H), 3.88 (s, 3 H), 3.82 (s, 3 H), 2.41 (s, 3 H), 2.39 (s, 3 H); ¹³C NMR (CDCl₃) δ 162.7, 162.6, 160.0, 150.4, 148.8, 148.5, 140.6, 140.1, 136.3, 134.1, 131.6, 129.5, 129.2, 129.0, 128.5, 123.0, 122.1, 118.4, 118.3, 112.6, 111.1, 110.7, 92.6, 92.4, 55.9, 55.9, 55.8, 21.3, 21.2; Anal. Calcd for C₁₈H₁₇NO₂. Theoretical: C, 77.40; H, 6.13; N, 5.01. Found: C, 77.64; H, 5.93; N, 5.01.

EXAMPLE 13

3-(4-Biphenylyl)-3-(3,4-dimethoxyphenyl)acrylonitrile

A. 3,4-Dimethoxy-4'-phenylbenzophenone

[0068] 3,4-Dimethoxy-4'-phenylbenzophenone was prepared analogously to 3,4,3',4'-tetramethoxybenzophenone using veratrole (2.4 g, 17 mmol), aluminum chloride (2.5 g, 19 mmol) and 4-biphenylcarbonyl chloride (4 g, 18 mmol) with a reaction time of 24 hours at room temperature. The crude product was purified by flash column chromatography (silica gel, 2% ethyl acetate/methylene chloride) to afford 3.86 g (70%) of the product as a white solid: mp 103-104 °C; ¹H NMR (CDCl₃) δ 7.88-7.84 (m, 2 H), 7.73-7.64 (m, 4 H), 7.52-7.40 (m, 5 H), 6.93-6.90 (m, 1 H), 3.97 (s, 3 H), 3.96 (s, 3 H); ¹³C NMR (CDCl₃) δ 194.9, 152.9, 148.9, 144.5, 139.8, 136.8, 130.2, 130.2, 128.8, 127.9, 127.1, 126.7, 125.2, 112.0, 109.7, 55.9, 55.9; Anal. Calcd for C₂₁H₁₈O₃. Theoretical: C, 79.23; H, 5.70. Found: C, 78.91; H, 5.87.

B. 3-(4-Biphenylyl)-3-(3,4-dimethoxyphenyl)acrylonitrile

[0069] 3-(4-Biphenylyl)-3-(3,4-dimethoxyphenyl)acrylonitrile was prepared analogously to methyl 3,3-bis-(3',4'-dimethoxyphenyl)acrylate using 3,4-dimethoxy-4'-phenylbenzophenone (2.33 g, 7.32 mmol), diethylcyanomethylphosphonate (1.5 mL, 8.1 mmol) and lithium hexamethyldisilazide (8.1 mL, 8.1 mmol, 1M) with a reaction time of 22 hours. The crude product was purified by chromatography (silica gel, 1% ethyl acetate/methylene chloride) to afford 1.76 g (70%) of a mixture of the E and Z isomers as a white solid: mp 132.0-134 °C; ¹H NMR (CDCl₃) δ 7.70-7.39 (m, 18 H), 7.10-6.80 (m, 6 H), 5.69 (s, 1 H), 5.68 (s, 1 H), 3.95 (s, 6 H), 3.93 (s, 3 H), 3.89 (s, 3 H), 3.85 (s, 3 H); ¹³C NMR (CDCl₃) δ 162.2, 151.1, 148.8, 148.6, 143.0, 142.6, 140.0, 137.9, 135.9, 131.4, 130.1, 129.3, 129.1, 128.8, 128.8, 127.9, 127.1, 127.0, 126.0, 126.9, 123.1, 122.2, 118.3, 118.2, 112.6, 111.1, 110.7, 93.2, 92.9, 56.0, 55.9, 55.8; Anal. Calcd for C₂₃H₁₉NO₂. Theoretical: C, 80.92; H, 5.61; N, 4.10. Found: C, 80.55; H, 5.80; N, 3.95.

EXAMPLE 14

3-(3,4-Dimethoxyphenyl)-3-(4'-fluorophenyl)acrylonitrile

[0070] 3-(3,4-Dimethoxyphenyl)-3-(4'-fluorophenyl)acrylonitrile was prepared analogously to methyl 3,3-bis-(3,4-dimethoxyphenyl)acrylate using 3,4-dimethoxy-4'-fluorobenzophenone (1.3 g, 5 mmol), diethylcyanomethylphosphonate (0.91 mL, 5.5 mmol) and lithium hexamethyldisilazide (5.5 mL, 5.5 mmol, 1M) with a reaction time of 22 hours at room temperature. The crude product was purified by chromatography (silica gel, 1% ethyl acetate/methylene chloride) to afford 2.38 g (55%) of a mixture of the E and Z isomers as a white solid: mp 100-102°C; ¹H NMR (CDCl₃) δ 7.54-6.74 (m, 14 H), 5.67 (s, 1 H), 5.57 (s, 1 H), 3.94 (s, 3 H), 3.92 (s, 3 H), 3.87 (s, 3 H), 3.83 (s, 3 H); ¹³C NMR (CDCl₃) δ 166.0, 165.6, 162.0, 161.6, 151.3, 150.7, 148.9, 148.7, 135.4, 135.4, 133.2, 133.1, 131.7, 131.6, 131.3, 130.7, 130.5, 129.2, 123.1, 122.1, 118.1, 118.0, 115.8, 115.8, 115.5, 115.4, 112.6, 111.0, 110.8, 93.4, 93.2, 56.0, 56.0, 55.9; Anal. Calcd for C₁₇H₁₄FNO₂. Theoretical: C, 72.07; H, 4.98; N, 4.94. Found: C, 71.91; H, 4.98; N, 4.79.

EXAMPLE 15

3-(3,4-Dimethoxyphenyl)-3-naphth-2-ylacrylonitrile (E and Z Isomers)

A. 2-(3,4-Dimethoxybenzoyl)naphthalene

[0071] 2-(3,4-Dimethoxybenzoyl)naphthalene was prepared analogously to 3,4,3',4'-tetramethoxybenzophenone using veratrole (2.6 mL, 20 mmol), aluminum chloride (2.9 g, 22 mmol) and 2-naphthoyl chloride (3.9 g, 20 mmol) with a reaction time of 4 hours at reflux. The crude product was purified by flash column chromatography (silica gel, 2.5% ethyl acetate/methylene chloride) to afford 4.52 g (77%) of the product as a white solid: mp 120-121.5 °C; ¹H NMR (CDCl₃) δ 8.24 (s, 1 H), 8.03-7.84 (m, 4 H), 7.68-7.40 (m, 4 H), 7.00-6.87 (m, 1 H), 3.97 (s, 3 H), 3.95 (s, 3 H); ¹³C NMR (CDCl₃) δ 195.5, 153.0, 149.0, 135.5, 134.9, 132.2, 131.0, 130.4, 129.2, 128.1, 128.0, 127.8, 126.7, 125.9, 125.4, 112.2, 109.8, 56.1, 56.0; Anal. Calcd for C₁₉H₁₆O₃. Theoretical: C, 78.06; H, 5.52. Found: C, 77.73; H, 5.69.

B. 3-(3,4-Dimethoxyphenyl)-3-naphth-2-ylacrylonitrile

[0072] 3-(3,4-Dimethoxyphenyl)-3-naphth-2-ylacrylonitrile was prepared analogously to methyl 3,3-bis-(3',4'-dimethoxyphenyl)acrylate using 2-(3,4-dimethoxybenzoyl)naphthalene (2.9 g, 10 mmol), diethylcyanomethylphosphonate (1.8 mL, 11 mmol) and lithium hexamethyldisilazide (8.5 mL, 11 mmol, 1.3M) with a reaction time of 1 hour at reflux. The crude product was purified by chromatography (silica gel, methylene chloride) to afford 2.93 g (93%) of a mixture of the E and Z isomers as a white solid: mp 121-123 °C; ¹H NMR (CDCl₃) δ 8.11-6.78 (m, 20 H), 5.76 (s, 1 H), 5.75 (s, 1 H), 3.96 (s, 3 H), 3.92 (s, 3 H), 3.85 (s, 3 H), 3.80 (s, 3 H); ¹³C NMR (CDCl₃) δ 162.7, 162.7, 151.2, 150.6, 148.9, 148.7, 136.6, 134.5, 134.0, 133.8, 132.8, 131.5, 129.7, 129.4, 129.0, 128.6, 128.6, 128.3, 128.1, 127.7, 127.7, 127.4, 127.2, 126.8, 126.6, 125.4, 123.2, 122.2, 118.4, 118.2, 112.7, 111.1, 110.8, 93.9, 93.4, 56.0, 56.0, 55.9; Anal. Calcd for C₂₁H₁₇NO₂. Theoretical: C, 79.98; H, 5.43; N, 4.44. Found: C, 79.90; H, 5.65; N, 4.46.

EXAMPLE 16

3-(3,4-Dimethoxyphenyl)-3-(3,4-methylenedioxyphenyl)acrylonitrile

(E and Z Isomers)

A. 1-(3,4-Dimethoxybenzoyl)-3,4-methylenedioxybenzene

[0073] 1-(3,4-Dimethoxybenzoyl)-3,4-methylenedioxybenzene was prepared analogously to 3,4,3',4'-tetrarnethoxybenzophenone using veratrole (1.3 mL, 10 mmol), aluminum chloride (1.5 g, 11 mmol) and piperonyloyl chloride (1.9 g, 10 mmol) with a reaction time of 2.5 hours at room temperature. The crude product was purified by flash column chromatography (silica gel, 5% ethyl acetate/methylene chloride) to afford 1.99 g (69%) of the product as a white solid: mp 164-165°C; ¹H NMR (CDCl₃) δ 7.46-7.26 (m, 4 H), 6.95-6.82 (m, 2 H), 6.06 (s, 2 H), 3.96 (s, 3 H), 3.94 (s, 3 H); ¹³C NMR (CDCl₃) δ193.9, 152.7, 151.0, 148.9, 147.8, 132.4, 130.6, 126.1, 124.8, 112.2, 109.9, 109.7, 107.6, 101.7, 56.0, 56.0; Anal. Calcd for C₁₆H₁₄O₅. Theoretical: C, 67.13; H, 4.93. Found: C, 66.86; H, 5.11.

B. 3-(3,4-Dimethoxyphenyl)-3-(3,4-methylenedioxyphenyl)acrylonitrile

[0074] 3-(3,4-Dimethoxyphenyl)-3-(3,4-methylenedioxyphenyl)acrylonitrile was prepared analogously to methyl 3,3-bis-(3',4'-dimethoxyphenyl)acrylate using 1-(3,4-dimethoxybenzoyl)-3,4-methylenedioxybenzene (1.43 g, 5 mmol), diethylcyanomethylphosphonate (0.91 mL, 5.5 mmol) and lithium hexamethyldisilazide (4.2 mL, 5.5 mmol, 1.3M) with a reaction time of 1 hour at reflux and 24 hours at room temperature. The crude product was purified by chromatography (silica gel, 2% ethyl acetate/methylene chloride) to afford 0.79 g (51%) of a mixture of the E and Z isomers as an off white solid: mp 121-123 °C; ¹H NMR (CDCl₃) δ 7.10-6.73 (m, 12 H), 6.13-5.94 (m, 4 H), 5.57 (s, 1 H), 5.53 (s, 1 H), 3.94 (s, 3 H), 3.92 (s, 3 H), 3.87 (s, 3 H), 3.84 (s, 3 H); ¹³C NMR (CDCl₃) δ 162.3, 151.0, 150.5, 149.6, 149.1, 148.8, 148.5, 147.9, 133.2, 131.6, 130.8, 129.4, 124.3, 123.5, 123.1, 122.1, 118.5, 118.3, 112.6, 111.1, 110.7, 109.9, 108.5, 108.2, 101.6, 101.5, 92.2, 92.2, 56.0, 55.9, 55.9; Anal. Calcd for C₁₈H₁₅NO₄. Theoretical: C, 69.89; H, 4.89; N, 4.53. Found: C, 69.61; H, 5.01; N, 4.37.

EXAMPLE 17

3-(3,4-Dimethoxyphenyl)-3-pyridin-4-ylacrylonitrile (E and Z Isomers)

A. 4-(3,4-Dimethoxybenzoyl)pyridine

[0075] A hexane solution of butyl lithium (9 mL, 22 mmol, 2.5M) was slowly added to a stirring solution of 4-bromoveratrole (2.9 mL, 20 mmol) in 40 mL of tetrahydrofuran under nitrogen at -70 °C. After 15 minutes a solution of 4-cyanopyridine in 12 mL of tetrahydrofuran was added to the reaction mixture and stirring was continued for 45 minutes. The reaction was then allowed to warm to -10 °C and the reaction was carefully quenched with hydrochloric acid (45 mL, 1N). The mixture was stirred for 30 minutes at room temperature. The pH was then adjusted to 12 with 50 mL of a 10% aqueous solution of sodium hydroxide. The mixture was extracted with ether (3 x 50 mL). The combined ethereal extracts were washed with brine (100 mL) then dried over magnesium sulfate and concentrated in vacuo to a brown solid. The crude product was purified by flash column chromatography (silica gel, 3% methanol/methylene chloride) to afford after vacuum drying (60°C, 1 mm) 1.9 g (39%) of the product: mp 117-118°C; ¹H NMR (CDCl₃) δ 8.85-8.76 (m, 2 H), 7.60-7.50 (m, 3 H), 7.40-7.30 (m, 1 H), 6.97-6.88 (m, 1 H), 3.98 (s, 3 H), 3.96 (s, 3 H); ¹³C NMR (CDCl₃) δ 193.7, 153.9, 150.1, 149.3, 145.2, 128.7, 125.9, 122.6, 111.5, 109.9, 56.1, 56.0; Anal. Calcd for C₁₄H₁₃NO₃. Theoretical: C, 69.12; H, 5.39; N, 5.76. Found: C, 69.05; H, 5.39; N, 5.85.

B. 3-(3,4-Dimethoxyphenyl)-3-pyridin-4-ylacrylonitrile

[0076] 3-(3,4-Dimethoxyphenyl)-3-pyridin-4-ylacrylonitrile was prepared analogously to methyl 3,3-bis-(3',4'-dimethoxyphenyl)acrylate using 4-(3,4-dimethoxybenzoyl)pyridine (1 g, 4 mmol), diethylcyanomethylphosphonate (0.73 mL, 4.4 mmol) and lithium hexamethyldisilazide (3.4 mL, 4.4 mmol, 1.3M) with a reaction time of 24 hours at room temperature. The crude product was slurried in 10 mL of hexane. The mixture was filtered, the solid was washed with hexane, air dried and then dried in vacuo to afford 0.91 g (85%) of a mixture of the E and Z isomers as an off white solid: mp 116-125°C; ¹H NMR (CDCl₃) δ 8.80-8.63 (m, 4 H), 7.40-7.20 (m, 4 H), 7.04-6.74 (m, 6 H), 5.81 (s, 1 H), 5.70 (s, 1 H), 3.94 (s, 3 H), 3.92 (s, 3 H), 3.87 (s, 3 H), 3.84 (s, 3 H); ¹³C NMR (CDCl₃) δ 160.1, 157.0, 151.6, 151.1, 150.3, 149.2, 148.9, 146.7, 144.9, 129.6, 127.8, 123.7, 123.1, 122.7, 122.1, 117.4, 117.1, 112.3, 111.0, 110.5, 96.1, 94.8, 56.0, 56.0; Anal. Calcd for C₁₆H₁₄N₂O₂. Theoretical: C, 72.17; H, 5.30; N, 10.52. Found: C, 72.35; H, 5.43; N, 10.47.

EXAMPLE 18

3-(3,4-Dimethoxyphenyl)-3-pyridin-2-ylacrylonitrile

A. 2-(3,4-Dimethoxybenzoyl)pyridine

[0077] 2-(3,4-Dimethoxybenzoyl)pyridine was prepared analogously to 4-(3,4-dimethoxybenzoyl)pyridine using 2-cyanopyridine. The crude mixture was purified by flash column chromatography (silica gel, 1% methanol/methylene chloride) to afford after drying in vacuo (60°C, 1 mm) 1.67 g (34%) of the product: mp 91.5-93 °C; ¹H NMR (CDCl₃) δ 8.76-8.70 (m, 1 H), 8.05-7.71 (m, 4 H), 7.55-7.45 (m, 1 H), 7.00-6.89 (m, 1 H), 3.96 (s, 3 H), 3.96 (s, 3 H); ¹³C NMR (CDCl₃) δ 192.1, 155.7, 153.3, 148.7, 148.2, 136.9, 128.9, 126.7, 125.7, 124.4, 112.6, 109.8, 56.0, 55.9; Anal. Calcd for C₁₄H₁₃NO₃. Theoretical: C, 69.12; H, 5.39; N, 5.76. Found: C, 68.96; H, 5.47; N, 5.66.

B. 3-(3,4-Dimethoxyphenyl)-3-pyridin-2-ylacrylonitrile

[0078] 3-(3,4-Dimethoxyphenyl)-3-pyridin-2-yl)acrylonitrile was prepared analogously to methyl 3,3-bis-(3',4'-dimethoxyphenyl)acrylate using 2-(3,4-dimethoxybenzoyl)pyridine (1 g, 4 mmol), diethylcyanomethylphosphonate (0.73 mL, 4.4 mmol) and lithium hexamethyldisilazide (3.4 mL, 4.4 mmol, 1.3M) with a reaction time of 17 hours at room temperature. The crude product was purified by flash column chromatography (silica gel, 1% methanol/methylene chloride) to afford 0.8 g (75%) of a mixture of the E and Z isomers as a brown solid. The isomers were separated by additional purification (silica gel, 10% ethyl acetate/methylene chloride) to afford pure samples of each of the isomers.

[0079] Isomer 1: mp 125-126 °C; ¹H NMR (CDCl₃) δ 8.75-8.65 (m, 1 H), 7.75-7.60 (m, 1 H), 7.41-7.16 (m, 2 H), 7.10-6.90 (m, 3 H), 6.52 (s, 1 H), 3.95 (s, 3 H), 3.89 (s, 3 H); ¹³C NMR (CDCl₃) δ 159.9, 154.9, 150.4, 149.9, 148.9, 136.7, 128.0, 124.6, 124.1, 122.6, 118.1, 112.4, 111.1, 97.8, 56.1, 56.0; Anal. Calcd for C₁₆H₁₄N₂O₂. Theoretical: C, 72.17; H, 5.30; N, 10.52. Found: C, 71.90; H, 5.28; N, 10.33.

[0080] Isomer 2: mp 134.5-135.5 °C; ¹H NMR (CDCl₃) δ 8.82-8.70 (m, 1 H), 7.88-7.76 (m, 1 H), 7.60-7.34 (m, 2 H), 6.94-6.80 (m, 3 H), 5.82 (s, 1 H), 3.91 (s, 3 H), 3.83 (s, 3 H); ¹³C NMR (CDCl₃) δ 160.8, 155.3, 151.2, 149.9, 149.0, 136.6, 130.2, 124.9, 124.3, 122.1, 117.6, 110.9, 95.4, 56.0; Anal. Calcd for C₁₆H₁₄N₂O₂. Theoretical: C, 72.17; H, 5.30; N, 10.52. Found: C, 72.13; H, 5.23; N, 10.40.

EXAMPLE 19

3-(3,4-Diethylphenyl)-3-phenylacrylonitrile (E and Z Isomers)

A. 3,4-Diethylbenzophenone

[0081] To a stirred ice bath cooled solution of diethylbenzene (1.7 mL, 10 mmol) in methylene chloride (30 mL) under nitrogen was added aluminum chloride (2.93 g, 22 mmol). A slight exotherm resulted. To the resulting reaction mixture was added benzoyl chloride (1.2 mL, 10 mmol). The reaction mixture was allowed to warm to room temperature and was then stirred at room temperature for 1.5 hours. The reaction mixture was poured into 60 mL of iced water and stirred for 20 minutes. The resulting mixture was extracted with methylene chloride (2 x 40 mL). The combined extracts were dried over magnesium sulfate and concentrated in vacuo to afford the crude product as an orange oil. The crude product was purified by flash column chromatography (silica gel, 2.5 % ethyl acetate/hexane) to afford 1.22 g (51%) of the product as a yellow oil: ¹H NMR (CDCl₃) δ 7.85-7.41 (m, 7 H), 7.30-7.20 (m, 1 H) 2.83-2.61(m, 4 H), 1.35-1.17 (m, 6 H); ¹³C NMR (CDCl₃) δ 196.8, 147.0, 141.9, 138.1, 135.3, 132.1, 132.1, 130.1, 130.0, 128.1, 128.1, 25.6, 25.4, 15.1, 15.0; Anal. Calcd for C₁₇H₁₈O. Theoretical: C, 85.67; H, 7.61. Found: C, 85.38; H, 7.42.

B. 3-(3,4-Diethylphenyl)-3-phenylacrylonitrile

[0082] 3-(3,4-Diethylphenyl)-3-phenylacrylonitrile was prepared analogously to methyl 3,3-bis-(3,4-dimethoxyphenyl)acrylate using 3,4-diethylbenzophenone (0.95 g, 4 mmol), diethylcyanomethylphosphonate (0.73 mL, 4.4 mmol) and lithium hexamethyldisilazide (3.4 mL, 4.4 mmol, 1.3M) with a reaction time of 2 hours at room temperature. The crude product was purified by flash chromatography (silica gel, 8% ethyl acetate/methylene chloride) to afford an oil which was stirred in hexane until it solidified. The resulting slurry was filtered, the solid washed with hexane, air dried and then dried in vacuo to afford 0.6 g (57%) of a mixture of the E and Z isomers as a white solid: mp 63-64 °C; ¹H NMR (CDCl₃) δ 7.51-6.99 (m, 16 H), 5.72 (s, 2 H), 2.76 -2.55 (m, 8 H), 1.32-1.14 (m, 12 H); ¹³C NMR (CDCl₃) δ 163.3, 144.7, 142.2, 137.3, 136.5, 130.2, 129.8, 129.6, 128.6, 128.5, 128.4, 128.3, 127.2, 126.2, 118.2, 93.9, 93.7, 25.5, 25.3, 15.2, 15.0.

EXAMPLE 20

3-(3,4-Diethylphenyl)-3-(3,4-dimethoxyphenyl)acrylonitrile

A. 3',4'-Diethyl-3,4-dimethoxybenzophenone

[0083] 3',4'-Diethyl-3,4-dimethoxybenzophenone was prepared analogously to 3,4-diethylbenzophenone using diethylbenzene (2.5 mL, 15 mmol), aluminum chloride (2.2 g, 16.5 mmol) and 3,4-dimethoxybenzoyl chloride (3 g, 15 mmol) with a reaction time of 3 hours at reflux. The crude product was purified by flash column chromatography (silica gel, 1.5 % ethyl acetate/hexane) to afford 0.84g (20%) of the product as an orange solid: mp 60-61 °C; ¹H NMR (CDCl₃) δ 7.74-7.15 (m, 5 H), 7.00-6.80 (m, 1 H) 3.96 (s, 3 H), 3.94 (s, 3 H), 2.93-2.60 (m, 4 H), 1.43-1.15 (m, 6 H); ¹³C NMR (CDCl₃) δ 195.5, 152.7, 148.8, 146.3, 141.7, 135.9, 130.6, 129.8, 128.0, 127.7, 125.1, 112.2, 109.7, 56.0, 25.6, 25.4, 15.1, 15.0; Anal. Calcd for C₁₉H₂₂O₃. Theoretical: C, 76.48; H, 7.43. Found: C, 76.53; H, 7.34.

B. 3-(3,4-Diethylphenyl)-3-(3,4-dimethoxyphenyl)acrylonitrile

[0084] 3-(3,4-Diethylphenyl)-3-(3,4-dimethoxyphenyl)acrylonitrile was prepared analogously to methyl 3,3-bis-(3,4-dimethoxyphenyl)acrylate using 3',4'-diethyl-3,4-dimethoxybenzophenone (0.51 g, 1.7 mmol), diethylcyanomethylphosphonate (0.31 mL, 1.9 mmol) and lithium hexamethyldisilazide (1.4 mL, 1.9 mmol, 1.3M) with a reaction time of 60 hours at room temperature. The crude product was purified by chromatography (silica gel, 1% ethyl acetate/methylene chloride) to afford an oil which was stirred in hexane until it solidified. The resulting slurry was filtered, the solid washed with hexane, air dried, and dried in vacuo to afford 0.31 g (57%) of a mixture of the E and Z isomers as an off white solid: mp 78-82 °C; ¹H NMR (CDCl₃) δ 7.30-6.75 (m, 12 H), 5.61 (s, 1 H), 5.60 (s, 1 H), 3.94 (s, 3 H), 3.92 (s, 3 H), 3.87 (s, 3 H), 3.83 (s, 3 H), 2.80-2.59 (m, 8 H), 1.35-1.14 (m, 12 H); ¹³C NMR (CDCl₃) δ 163.0,163.0, 151.0, 150.5, 148.8, 148.6, 144.6, 143.9, 142.1, 141.8, 136.8, 134.5, 131.9, 129.7, 128.6, 128.5, 128.2, 127.3, 126.3, 123.2, 122.2, 118.7, 118.6, 112.8, 111.3, 110.7, 92.5, 92.2, 56.1, 56.0, 25.5, 25.4, 25.4, 25.3, 15.3, 15.2, 15.0, 14,9; Anal, Calcd for C₂₁H₂₃NO₂. Theoretical: C, 78.47; H, 7.21; N, 4.36. Found: C, 77.80; H, 7.25; N, 4.68.

EXAMPLE 21

4-(3-Ethoxy-4-methoxypbenyl)-4-phenyl-3-butan-2-one

[0085] To a suspension of cuprous cyanide (0.21 g, 2.3 mmol) in tetrahydrofuran (8 mL) at -70 °C under nitrogen was added a cyclohexyl/ether solution of phenyl lithium (2.6 mL, 4.6 mmol, 1.8M). After 45 minutes a solution of 4-(3-ethoxy-4-methoxyphenyl)-3-buten-2-one (0.51 g, 2,3 mmol) in 10 mL of tetrahydrofuran was slowly added to the reaction mixture. After 1 hour at -78 °C the mixture was allowed to warm to room temperature. The reaction mixture was then carefully quenched with 10 mL of an aqueous solution of ammonium chloride. The resulting mixture was extracted with methylene chloride (3 x 10 mL). The combined organic extracts were dried over magnesium sulfate and concentrated in vacuo to afford 0.7 g of the crude product. The crude product was purified by chromatography (silica gel, 2% ethyl acetate/methylene chloride) to afford 0.41 g (60%) of the product as an oil which solidified: mp 57-58 °C; ¹H NMR (CDCl₃) δ 7.31-7.13 (m, 5 H), 6.83-6.69 (m, 3 H), 4.48 (t, J = 7.5 Hz, 1 H), 4.03 (q, J = 7 Hz, 2 H), 3.82 (s, 3 H), 3.13 (d, J = 7.5 Hz, 2 H), 2.07 (s, 3 H), 1.41 (t, J = 7 Hz, 3 H); ¹³C NMR (CDCl₃) δ 207.0, 148.2, 148.0, 144.2, 136.4, 128.6, 127.6, 126.4, 119.4, 113.0, 111.5, 64.3, 55.9, 49.9, 45.6, 30.6, 14.8; Anal. Calcd for C₁₉H₂₂O₃. Theoretical: C, 76.48; H, 7.43. Found: C, 76.81; H, 7.44.

EXAMPLE 22

3-(3,4-Dimethoxyphenyl)-3-(naphth-1-yl)acrylonitrile

[0086] 1-(3,4-Dimethoxybenzoyl)naphthalene was prepared analogously to 3,4,3',4'-tetramethoxybenzophenone using veratrole (1.3 mL, 10 mmol), aluminum chloride (1.5 g, 11 mmol) and 1-naphthoyl chloride (1.5 mL, 10 mmol) with a reaction time of 24 hours at room temperature. The crude product was purified by flash column chromatography (silica gel, 2.5% ethyl acetate/methylene chloride) to afford 1.85 g (63%) of the product as a white solid: mp 92.5-94.5°C; ¹H NMR (CDCl₃) δ 8.06-7.84 (m, 3 H), 7.80-7.39 (m, 5 H), 7.31-7.21 (m, 1 H), 6.84-6.74 (m, 1 H), 3.94 (s, 3 H), 3.91 (s, 3 H); ¹³C NMR (CDCl₃) δ 196.6, 153.5, 149.0, 136.8, 133.6, 131.1, 130.9, 130.5, 128.2, 126.9, 126.7, 126.3, 126.3, 125.6, 124.3, 111.3, 109.7, 56.0, 55.9; Anal. Calcd for C₁₉H₁₆O₃. Theoretical: C, 78.06; H, 5.52. Found: C, 77.97; H, 5.66.
   3-(3,4-Dimethoxyphenyl)-3-(naphth-1-yl)acrylonitrile is prepared in a fashion similar to that described in Example 15.

EXAMPLE 23

3-(3,4-Dimethoxyphenyl)-3-(2,5-dichlorophenyl)acrylonitrile

[0087] 2',5'-Dichloro-3,4-dimethoxybenzophenone was prepared analogously to 3,4,3',4'-tetramethoxybenzophenone using veratrole (2.15 mL, 15 mmol), aluminum chloride (2.2 g, 16.5 mmol) and 2,5-dichlorobenzoyl chloride (1.9 mL, 15 mmol) with a reaction time of 3 hours at reflux. The crude product was purified by flash column chromatography (silica gel, 2.5% ethyl acetate/methylene chloride) to afford 3.88 g (83%) of the product as a white solid: mp 129-130°C; ¹H NMR (CDCl₃) δ 7.65-7.56 (m, 1 H), 7.41-7.12 (m, 4 H), 6.89-6.81 (m, 1 H), 3.96 (s, 3 H), 3.94 (s, 3 H); ¹³C NMR (CDCl₃) δ 191.1, 154.4, 149.6, 137.9, 132.0, 130.5, 128.7, 128.0, 125.7, 110.2, 56.1, 56.0; Anal. Calcd for C₁₅H₁₂Cl₂O₃. Theoretical: C, 57.90; H, 3.89. Found: C, 57.58; H, 3.87.
   3-(3,4-Dimethoxyphenyl)-3-(2,5-dichlorophenyl)acrylonitrile is prepared in an analogous fashion as described in Example 20 starting with 5'-dichloro-3,4-dimethoxybenzophenone.

EXAMPLE 24

[0088] Tablets, each containing 50 milligrams of active ingredient, can be prepared in the following manner:

Constituents (for 1000 tablets)
active ingredient	50.0 grams
lactose	50.7 grams
wheat starch	7.5 grams
polyethylene glycol 6000	5.0 grams
talc	5.0 grams
magnesium stearate	1.8 grams
demineralized water	q.s.

[0089] The solid ingredients are first forced through a sieve of 0.6 mm mesh width. The active ingredient, the lactose, the talc, the magnesium stearate and half of the starch then are mixed. The other half of the starch is suspended in 40 milliliters of water and this suspension is added to a boiling solution of the polyethylene glycol in 100 milliliters of water. The resulting paste is added to the pulverulent substances and the mixture is granulated, if necessary with the addition of water. The granulate is dried overnight at 35°C, forced through a sieve of 1.2 mm mesh width and compressed to form tablets of approximately 6 mm diameter which are concave on both sides.

EXAMPLE 25

[0090] Tablets, each containing 100 milligrams of active ingredient, can be prepared in the following manner:

Constituents (for 1000 tablets)
active ingredient	100.0 grams
lactose	100.0 grams
wheat starch	47.0 grams
magnesium stearate	3.0 grams

[0091] All the solid ingredients are first forced through a sieve of 0.6 mm mesh width. The active ingredient, the lactose, the magnesium stearate and half of the starch then are mixed. The other half of the starch is suspended in 40 milliliters of water and this suspension is added to 100 milliliters of boiling water. The resulting paste is added to the pulverulent substances and the mixture is granulated, if necessary with the addition of water. The granulate is dried overnight at 35°C, forced through a sieve of 1.2 mm mesh width and compressed to form tablets of approximately 6 mm diameter which are concave on both sides.

EXAMPLE 26

[0092] Tablets for chewing, each containing 75 milligrams of active ingredient, can be prepared in the following manner:

Composition (for 1000 tablets)
active ingredient	75.0 grams
mannitol	230.0 grams
lactose	150.0 grams
talc	21.0 grams
glycine	12.5 grams
stearic acid	10.0 grams
saccharin	1.5 grams
5% gelatin solution	q.s.

[0093] All the solid ingredients are first forced through a sieve of 0.25 mm mesh width. The mannitol and the lactose are mixed, granulated with the addition of gelatin solution, forced through a sieve of 2 mm mesh width, dried at 50°C and again forced through a sieve of 1.7 mm mesh width. The active ingredient, the glycine and the saccharin are carefully mixed, the mannitol, the lactose granulate, the stearic acid and the talc are added and the whole is mixed thoroughly and compressed to form tablets of approximately 10 mm diameter which are concave on both sides and have a breaking groove on the upper side.

EXAMPLE 27

[0094] Tablets, each containing 10 milligrams of active ingredient, can be prepared in the following manner:

Composition (for 1000 tablets)
active ingredient	10.0 grams
lactose	328.5 grams
corn starch	17.5 grams
polyethylene glycol 6000	5.0 grams
talc	25.0 grams
magnesium stearate	4.0 grams
demineralized water	q.s.

[0095] The solid ingredients are first forced through a sieve of 0.6 mm mesh width. Then the active ingredient, lactose, talc, magnesium stearate and half of the starch are intimately mixed. The other half of the starch is suspended in 65 milliliters of water and this suspension is added to a boiling solution of the polyethylene glycol in 260 milliliters of water. The resulting paste is added to the pulverulent substances, and the whole is mixed and granulated, if necessary with the addition of water. The granulate is dried overnight at 35°C, forced through a sieve of 1.2 mm mesh width and compressed to form tablets of approximately 10 mm diameter which are concave on both sides and have a breaking notch on the upper side.

EXAMPLE 28

[0096] Gelatin dry-filled capsules, each containing 100 milligrams of active ingredient, can be prepared in the following manner

Composition (for 1000 capsules)
active ingredient	100.0 grams
microcrystalline cellulose	30.0 grams
sodium lauryl sulphate	2.0 grams
magnesium stearate	8.0 grams

[0097] The sodium lauryl sulphate is sieved into the active ingredient through a sieve of 0.2 mm mesh width and the two components are intimately mixed for 10 minutes. The microcrystalline cellulose is then added through a sieve of 0.9 mm mesh width and the whole is again intimatelymixed for 10 minutes. Finally, the magnesium stearate is added through a sieve of 0.8 mm width and, after mixing for a further 3 minutes, the mixture is introduced in portions of 140 milligrams each into size 0 (elongated) gelatin dry-fill capsules.

EXAMPLE 29

[0098] A 0.2% injection or infusion solution can be prepared, for example, in the following manner:

active ingredient	5.0 grams
sodium chloride	22.5 grams
phosphate buffer pH 7.4	300.0 grams
demineralized water to 2500.0 milliliters

[0099] The active ingredient is dissolved in 1000 milliliters of water and filtered through a microfilter or slurried in 1000 mL of H₂O. The buffer solution is added and the whole is made up to 2500 milliliters with water. To prepare dosage unit forms, portions of 1.0 or 2.5 milliliters each are introduced into glass ampoules (each containing respectively 2.0 or 5.0 milligrams of active ingredient).

Claims

1. A compound of the formula:

in which:

R²   is hydrogen, nitro, cyano, trifluoromethyl, carboethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino, alkyl of 1 to 6 carbon atoms, alkylidenemethyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms or halo; with the proviso that either R¹ is selected from a group consisting of alkoxy of 1 to 6 carbon atoms, cycloalkoxy of from 3 to 10 carbon atoms and cyclopentylidenemethyl, and R² is alkoxy of 1 to 6 carbon atoms; or, R³ is phenyl independently substituted at the 3- and 4-positions with alkoxy up to 10 carbon atoms or cycloalkoxy of up to 10 carbon atoms; and,

R³   is (i) phenyl, substituted or unsubstituted with 1 or more substituents each selected independently from a group consisting of nitro, cyano, halo, trifluoromethyl, carboethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, or carbamoyl substituted with alkyl of 1 to 3 carbon atoms, acetoxy, carboxy, hydroxy, amino, amino substituted with an alkyl of 1 to 5 carbon atoms, alkyl of up to 10 carbon atoms, cycloalkyl of up to 10 carbon atoms, alkoxy of up to 10 carbon atoms, cycloalkoxy of up to 10 carbon atoms, alkylidenemethyl of up to 10 carbon atoms, cycloalkylidenemethyl of up to 10 carbon atoms, phenyl or methylenedioxy; (ii) pyridine, substituted pyridine, 2- or 3- pyrrolidene, imidazole, naphthalene, or thiophene; (iii) cycloalkyl of 4 to 10 carbon atoms, unsubstituted or substituted with one or more substituents each selected independently from the group consisting of nitro, cyano, halo, trifluoromethyl, carboethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino, substituted amino, alkyl of 1 to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms, phenyl;

each of R⁴ and R⁵ taken individually is a hydrogen or R⁴ and R⁵ together are a carbon-carbon bond; wherein,

Y   is CN;

R¹   is R⁸, (CH₂)_nR⁸, OR⁸, CH=CHR⁸, or CH=C(R¹⁰)₂ with the proviso that R³ cannot be unsubstituted phenyl when R¹ is methyl and R² is hydroxy;

R⁸   is methyl or R⁹;

R⁹   is alkyl of 2 to 10 carbon atoms, monocycloalkyl of 3 to 10 carbon atoms, polycycloalkyl of up to 10 carbon atoms, benzocycloalkyl of up to 10 carbons atoms;

R¹⁰   together with the carbon atom to which they are attached form a monocycloalkyl or bicycloalkyl group of up to 10 carbon atoms;

n   is 1 to 3;

or, alternatively, when each of R⁴ and R⁵ taken individually is hydrogen;

Y   is -CON(R⁶)₂, -CO₂H, -CO₂R⁷;

R¹   is -R⁹, -(CH₂)_nR⁸, -OR⁹, -CH=CHR⁸, or -CH=C(R¹⁰)₂;

R⁶   is hydrogen or alkyl of 1 to 6 carbon atoms;

R⁷   is alkyl of 1 to 6 carbon atoms or benzyl; or,

Y   is COR⁷;

R¹   is -R⁸, (CH₂)_nR⁸, OR⁸, CH=CHR⁸, or CH=C(R¹⁰)₂ with the proviso that R¹ and R² cannot be -OMe when R³ is hydroxy substituted phenyl;

2. A compound according to claim 1 where Y is -CN or COR⁷; R¹ is R⁸, (CH₂)_nR⁸, OR⁸; R² is hydrogen, nitro, cyano, trifluoromethyl, carboethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms or halo.

3. A compound according to claim 1 where Y is -CONR⁶R⁶, CO₂H or CO₂R⁷; R¹ is R⁹, (CH₂)_nR⁸, OR⁹; R² is hydrogen, nitro, cyano, trifluoromethyl, carboethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms or halo.

4. A compound according to claim 1 in which R³ is (i) phenyl or naphthalene, substituted or unsubstituted with 1 or more substituents each selected independently from a group consisting of nitro, cyano, halo, trifluoromethyl, carboethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, or carbamoyl substituted with alkyl of 1 to 3 carbon atoms, acetoxy, carboxy, hydroxy, amino, amino substituted with an alkyl of 1 to 5 carbon atoms, alkyl of up to 10 carbon atoms, cycloalkyl of up to 10 carbon atoms, alkoxy of up to 10 carbon atoms, cycloalkoxy of up to 10 carbon atoms, alkylidenemethyl up to 10 carbon atoms, cycloalkylidenemethyl of up to 10 carbon atoms, phenyl or methylenedioxy; or (ii) cycloalkyl of 4 to 10 carbon atoms, unsubstituted or substituted, nitro, cyano, halo, trifluoromethyl, carboethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino, substituted amino, alkyl of 1 to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms, phenyl.

5. A compound according to claim 1 which is a nitrile or ketone of the formula:

Y   is -CN or -COR⁷,

R¹   is R⁸, (CH₂)_nR⁸, OR⁸, CH=CHR⁸, or CH=C(R¹⁰)₂;

R²   is hydrogen, nitro, cyano, trifluoromethyl, carboethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms or halo;

R⁸   is methyl or R⁹;

R⁹   is alkyl of 2 to 10 carbon atoms, monocycloalkyl of 3 to 10 carbon atoms, polycycloalkyl of up to 10 carbon atoms, benzocycloalkyl of up to 10 carbon atoms;

R¹⁰   together with the carbon atom to which they are attached form a monocycloalkyl group.

6. A compound according to claim 1 which is a carboxylic acid, ester or amide of the formula:

   wherein:

Y   is -CO(NR⁶)₂, -CO₂H, -CO₂R⁷;

R¹   is R⁹, (CH₂)_nR⁸, OR⁹, CH=CHR⁸, or CH=C(R¹⁰)₂;

R⁶   is hydrogen or alkyl of 1 to 6 carbon atoms;

R⁷   is alkyl of 1 to 6 carbon atoms or benzyl;

R⁸   is methyl or R⁹;

R⁹   is alkyl of 2 to 10 carbon atoms, monocycloalkyl of 3 to 10 carbon atoms, polycycloalkyl of up to 10 carbon atoms, benzocycloalkyl of up to 10 carbon atoms; R¹⁰ together with the carbon atom to which they are attached form a monocycloalkyl or bicycloalkyl group; or,

n   is 1 to 3.

7. A compound according to claim 1 which is:

3,3-bis-(3,4-dimethoxyphenyl)acrylonitrile,

3,3-bis-(3-ethoxy-4-methoxyphenyl)acrylonitrile,

3-(3-propoxy-4-methoxyphenyl)-3-phenylacrylonitrile,

3-(3-ethoxy-4-methoxyphenyl)-3-phenylacrylonitrile,

3,3-bis-(3-cyclopentoxy-4-methoxyphenyl)acrylonitrile,

3-(3-cyclopentoxy-4-methoxyphenyl)-3-phenylacrylonitrile, 3-(3-cyclopentoxy-4-methoxyphenyl)-3-phenylpropanenitrile,

methyl 3-(3-cyclopentoxy-4-methoxyphenyl)-3-phenylpropanoate,

3-(3-ethoxy-4-methoxyphenyl)-3-phenylpropanenitrile,

methyl 3-(3-ethoxy-4-methoxyphenyl)-3-phenylpropanoate,

3,3-bis-(3,4-dimethoxyphenyl)propanenitrile,

3,3-bis-(3-ethoxy-4-methoxyphenyl)propanenitrile,

3-(3,4-dimethoxyphenyl)-3-phenylacrylonitrile,

3-(3-ethoxy-4-methoxyphenyl)-3-naphthylpropanenitrile,

3-(3,4-dimethoxyphenyl)-3-phenylpropanenitrile, or

3-(3,4-dimethoxyphenyl)-3-(3-ethoxy-4-methoxyphenyl)propanenitrile.

8. A compound according to claim 1 which is:

4-(3-ethoxy-4-methoxyphenyl)-4-(4-pyridyl)butan-2-one;

4-(3-cyclopentoxy-4-methoxyphenyl)-4-(4-pyridyl)butan-2-one;

methyl 3-(3-ethoxy-4-methoxyphenyl)-3-(4-pyridyl)propanoate;

3-(3-ethoxy-4-methoxyphenyl)-3-(4-pyridyl)prop-2-enenitrile;

3-(3-ethoxy-4-methoxyphenyl)-3-(4-pyridyl)propanenitrile;

3-(3-cyclopentoxy-4-methoxyphenyl)-3-(4-pyridyl)prop-2-enenitrile;

3-(3-cyclopentoxy-4-methoxyphenyl)-3-(4-pyridyl)propanenitrile;

4,4-bis-(3,4-dimethoxyphenyl)butan-2-one;

4-(3,4-dimethoxyphenyl)-4-(3-ethoxy-4-methoxyphenyl)butan-2-one;

4-(3,4-dimethoxyphenyl)-4-(3-(cyclopentylidenemethyl)-4-methoxyphenyl)butan-2-one;

3-(3,4-dimethoxyphenyl)-3-(3-(cyclopentylidenemethyl)-4-methoxyphenyl)prop-2-enenitrile;

3-(3-(cyclopentylidenemethyl)-4-methoxyphenyl)-3-phenyl-prop-2-enenitrile;

1 -(3,4-dimethoxyphenyl)-1-(3-ethoxy-4-methoxyphenyl)pentan-3-one;

1,1-bis-(3,4-dimethoxyphenyl)pentan-3-one;

3-(3,4-dimethoxyphenyl)-3-(3-(cyclopentylidenemethyl)-4-methoxyphenyl)prop-2-enenitrile;

3-(3-(cyclopentylidenemethyl)-4-methoxyphenyl)-3-phenyl-propanenitrile;

3,3-bis-(3-(cyclopentylidenemethyl)-4-methoxyphenyl)propanenitrile;

3,3-bis-(3-(cyclopentylidenemethyl)-4-methoxyphenyl)prop-2-enenitrile;

3-(3-(cyclopentylidenemethyl)-4-methoxyphenyl-3-phenyl)propanamide;

3,3-bis-(3-(cyclopentylidenemethyl)-4-methoxyphenyl)propanamide;

3,3-bis-(3-ethoxy-4-methoxyphenyl)propanamide;

3,3-bis-(3,4-dimethoxyphenyl)propanamide;

3-(3,4-dimethoxyphenyl)-3-(4-methoxy-3-exo-norbornyloxyphenyl)prop-2-enenitrile;

3-(3,4-dimethoxyphenyl)-3-(3,4-methylenedioxyphenyl)prop-2-enenitrile;

3-(4-aminophenyl)-3-(3,4-dimethoxyphenyl)prop-2-enenitrile; or

3-(4-aminophenyl)-3-(3-ethoxy-4-dimethoxyphenyl)prop-2-enenitrile.

9. A compound for use as an immunotherapeutic agent for reduction of cytokine levels and precursors of the formula:

in which:

R²   is hydrogen, nitro, cyano, trifluoromethyl, carboethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino, alkyl of 1 to 6 carbon atoms, alkylidenemethyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms or halo; with the proviso that either R¹ is selected from a group consisting of alkoxy of 1 to 6 carbon atoms, cycloalkoxy of from 3 to 10 carbon atoms and cyclopentylidenemethyl, and R² is alkoxy of 1 to 6 carbon atoms; or, R³ is phenyl independently substituted at the 3- and 4-positions with alkoxy up to 10 carbon atoms or cycloalkoxy of up to 10 carbon atoms; and,

R³   is (i) phenyl, substituted or unsubstituted with 1 or more substituents each selected independently from a group consisting of nitro, cyano, halo, trifluoromethyl, carboethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, or carbamoyl substituted with alkyl of 1 to 3 carbon atoms, acetoxy, carboxy, hydroxy, amino, amino substituted with an alkyl of 1 to 5 carbon atoms, alkyl of up to 10 carbon atoms, cycloalkyl of up to 10 carbon atoms, alkoxy of up to 10 carbon atoms, cycloalkoxy of up to 10 carbon atoms, alkylidenemethyl of up to 10 carbon atoms, cycloalkylidenemethyl of up to 10 carbon atoms, phenyl or methylenedioxy; (ii) pyridine, substituted pyridine, 2- or 3- pyrrolidene, imidazole, naphthalene, or thiophene; (iii) cycloalkyl of 4 to 10 carbon atoms, unsubstituted or substituted nitro, cyano, halo, trifluoromethyl, carboethoxy, with one or more substituents each selected independently from the group consisting of carbomethoxy, carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino, substituted amino, alkyl of 1 to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms, phenyl;

each of R⁴ and R⁵ taken individually is a hydrogen or R⁴ and R⁵ together are a carbon-carbon bond; wherein,

Y   is CN;

R¹   is R⁸, (CH₂)_nR⁸, OR⁸, CH=CHR⁸, or CH=C(R¹⁰)₂ with the proviso that R³ cannot be unsubstituted phenyl when R¹ is methyl and R² is hydroxy; R⁸ is methyl or R⁹;

R⁹   is alkyl of 2 to 10 carbon atoms, monocycloalkyl of 3 to 10 carbon atoms, polycycloalkyl of up to 10 carbon atoms, benzocycloalkyl of up to 10 carbon atoms; R¹⁰ together with the carbon atom to which they are attached form a monocycloalkyl or bicycloalkyl group of up to 10 carbon atoms;

n   is 1 to 3;

or, alternatively, when each of R⁴ and R⁵ taken individually is hydrogen;

Y   is -CON(R⁶)₂, -CO₂H, -CO₂R⁷;

R¹ is -R⁹, -(CH₂)_nR⁸, -OR⁹, -CH=CHR⁸, or -CH=C(R¹⁰)₂;

R⁶ is hydrogen or alkyl of 1 to 6 carbon atoms;

R⁷ is alkyl of 1 to 6 carbon atoms or benzyl; or,

Y   is COR⁷;

R¹   is -R⁸, (CH₂)_nR⁸, OR⁸, CH=CHR⁸, or CH=C(R¹⁰)₂ with the proviso that R¹ and R² cannot be -OMe when R³ is hydroxy substituted phenyl.

10. A compound according to claim 9 where Y is -CN or COR⁷; R¹ is R⁸, (CH₂)_nR⁸, OR⁸; R² is hydrogen, nitro, cyano, trifluoromethyl, carboethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms or halo.

11. A compound according to claim 9 where Y is -CONR⁶R⁶, CO₂H or CO₂R⁷; R¹ is R⁹, (CH₂)_nR⁸, OR⁹; R² is hydrogen, nitro, cyano, trifluoromethyl, carboethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms or halo.

12. A compound according to claim 9 in which R³ is (i) phenyl or naphthalene, substituted or unsubstituted with 1 or more substituents each selected independently from a group consisting of nitro, cyano, halo, trifluoromethyl, carboethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, or carbamoyl substituted with alkyl of 1 to 3 carbon atoms, acetoxy, carboxy, hydroxy, amino, amino substituted with an alkyl of 1 to 5 carbon atoms, alkyl of up to 10 carbon atoms, cycloalkyl of up to 10 carbon atoms, alkoxy of up to 10 carbon atoms, cycloalkoxy of up to 10 carbon atoms, alkylidenemethyl up to 10 carbon atoms, cycloalkylidenemethyl of up to 10 carbon atoms, phenyl or methylenedoxy; or (ii) cycloalkyl of 4 to 10 carbon atoms, unsubstituted or substituted with one or more substituents each selected independently from the group consisting of nitro, cyano, halo, trifluoromethyl, carboethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino, substituted amino, alkyl of 1 to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms, phenyl.

13. A compound according to claim 9 which is a nitrile or ketone of formula:

Y   is -CN or -COR⁷,

R¹   is R⁸, (CH₂)_nR⁸, OR⁸, CH=CHR⁸, or CH=C(R¹⁰)₂;

R²   is hydrogen, nitro, cyano, trifluoromethyl, carboethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms or halo;

R⁸   is methyl or R⁹;

R⁹   is alkyl of 2 to 10 carbon atoms, monocycloalkyl of 3 to 10 carbon atoms, polycycloalkyl of up to 10 carbon atoms, benzocycloalkyl of up to 10 carbon atoms;

R¹⁰   together with the carbon atom to which they are attached form a monocycloalkyl group.

14. A compound according to claim 9 which is a carboxylic acid, ester or amide of the formula:

wherein:

Y   is -CO(NR⁶)₂, -CO₂H, -CO₂R⁷;

R¹   is R⁹, (CH₂)_nR⁸, OR⁹, CH=CHR⁸, or CH=C(R¹⁰)₂;

R⁶   is hydrogen or alkyl of 1 to 6 carbon atoms;

R⁷   is alkyl of 1 to 6 carbon atoms or benzyl;

R⁸   is methyl or R⁹;

R⁹   is alkyl of 2 to 10 carbon atoms, monocycloalkyl of 3 to 10 carbon atoms, polycycloalkyl of up to 10 carbon atoms, benzocycloalkyl of up to 10 carbon atoms;

R¹⁰   together with the carbon atom to which they are attached form a monocycloalkyl or bicycloalkyl group; or,

n   is 1 to 3.

15. A compound according to claim 9 which is:

3,3-bis-(3,4-dimethoxyphenyl)acrylonitrile,

3,3-bis-(3-ethoxy-4-methoxyphenyl)acrylonitrile,

3-(3-propoxy-4-methoxyphenyl)-3-phenylacrylonitrile,

3-(3-ethoxy-4-methoxyphenyl)-3-phenylacrylonitrile,

3,3-bis-(3-cyclopentoxy-4-methoxyphenyl)acrylonitrile,

3-(3-cyclopentoxy-4-methoxyphenyl)-3-phenylacrylonitrile,

3-(3-cyclopentoxy-4-methoxyphenyl)-3-phenylpropanenitrile,

methyl 3-(3-cyclopentoxy-4-methoxyphenyl)-3-phenylpropanoate,

3-(3-ethoxy-4-methoxyphenyl)-3-phenylpropanenitrile,

methyl 3-(3-ethoxy-4-methoxyphenyl)-3-phenylpropanoate,

3,3-bis-(3,4-dimethoxyphenyl)propanenitrile,

3,3-bis-(3-ethoxy-4-methoxyphenyl)propanenitrile,

3-(3,4-dimethoxyphenyl)-3-phenylacrylonitrile,

3-(3-ethoxy-4-methoxyphenyl)-3-naphthylpropanenitrile,

3-(3,4-dimethoxyphenyl)-3-phenylpropanenitrile, or

3-(3,4-dimethoxyphenyl)-3-(3-ethoxy-4-methoxyphenyl)propanenitrile.

16. A compound according to claim 9 which is:

4-(3-ethoxy-4-methoxyphenyl)-4-(4-pyridyl)butan-2-one;

44-(3-cyclopentoxy-4-methoxyphenyl)-4-(4-pyridyl)butan-2-one;

methyl 3-(3-ethoxy-4-methoxyphenyl)-3-(4-pyridyl)propanoate;

3-(3-ethoxy-4-methoxyphenyl)-3-(4-pyridyl)prop-2-enenitrile;

3-(3-ethoxy-4-methoxyphenyl)-3-(4-pyridyl)propanenitrile;

3-(3-cyclopentoxy-4-methoxyphenyl)-3-(4-pyridyl)prop-2-enenitrile;

3-(3-cyclopentoxy-4-methoxyphenyl)-3-(4-pyridyl)propanenitrile;

4,4-bis-(3,4-dimethoxyphenyl)butan-2-one;

4-(3,4-dimethoxyphenyl)-4-(3-ethoxy-4-methoxyphenyl)butan-2-one;

4-(3,4-dimethoxyphenyl)-4-(3-(cyclopentylidenemethyl)-4-methoxyphenyl)butan-2-one;

3-(3,4-dimethoxyphenyl)-3-(3-(cyclopentylidenemethyl)-4-methoxyphenyl)prop-2-enenitrile;

3-(3-(cyclopentylidenemethyl)-4-methoxyphenyl)-3-phenyl-prop-2-enenitrile;

1-(3,4-dimethoxyphenyl)-1-(3-ethoxy-4-methoxyphenyl)pentan-3-one;

1,1-bis-(3,4-dimethoxyphenyl)pentan-3-one;

3-(3,4-dimethoxyphenyl)-3-(3-(cyclopentylidenemethyl)-4-methoxyphenyl)prop-2-enenitrile;

3-(3-(cyclopentylidenemethyl)-4-methoxyphenyl)-3-phenyl-propanenitrile; 3,3-bis-(3-(cyclopentylidenemethyl)-4-methoxyphenyl)propanenitrile;

3,3-bis-(3-(cyclopentylidenemethyl)-4-methoxyphenyl)prop-2-enenitrile;

3-(3-(cyclopentylidenemethyl)-4-methoxyphenyl-3-phenyl)propanamide;

3,3-bis-(3-(cyclopentylidenemethyl)-4-methoxyphenyl)propanamide;

3,3-bis-(3-ethoxy-4-methoxyphenyl)propanamide;

3,3-bis-(3,4-dimethoxyphenyl)propanamide;

3-(3,4-dimethoxyphenyl)-3-(4-methoxy-3-exo-norbomyloxyphenyl)prop-2-enenitrile;

3-(3,4-dimethoxyphenyl)-3-(3,4-methylenedioxyphenyl)prop-2-enenitrile;

3-(4-aminophenyl)-3-(3,4-dimethoxyphenyl)prop-2-enenitrile; or

3-(4-aminophenyl)-3-(3-ethoxy-4-dimethoxyphenyl)prop-2-enenitrile.

Ansprüche

1. Verbindung der Formel:

in der:

R² Wasserstoff, Nitro, Cyano, Trifluormethyl, Carboethoxy, Carbomethoxy, Carbopropoxy, Acetyl, Carbamoyl, Acetoxy, Carboxy, Hydroxy, Amino, Alkyl mit 1 bis 6 Kohlenstoffatomen, Alkylidenmethyl mit 1 bis 6 Kohlenstoffatomen, Alkoxy mit 1 bis 6 Kohlenstoffatomen oder Halo ist; mit der Maßgabe, daß entweder R¹ ausgewählt ist aus einer Gruppe, die aus Alkoxy mit 1 bis 6 Kohlenstoffatomen, Cycloalkoxy mit von 3 bis 10 Kohlenstoffatomen und Cyclopentylidenmethyl besteht, und R² Alkoxy mit 1 bis 6 Kohlenstoffatomen ist; oder R³ Phenyl ist, unabhängig substituiert an den 3- und 4-Positionen mit Alkoxy mit bis zu 10 Kohlenstoffatomen oder Cycloalkoxy mit bis zu 10 Kohlenstoffatomen; und

R³ (i) Phenyl, substituiert oder unsubstituiert mit 1 oder mehr Substituenten, jeder unabhängig ausgewählt aus einer Gruppe, die aus Nitro, Cyano, Halo, Trifluormethyl, Carboethoxy, Carbomethoxy, Carbopropoxy, Acetyl, Carbamoyl oder Carbamoyl, substituiert mit Alkyl mit 1 bis 3 Kohlenstoffatomen, Acetoxy, Carboxy, Hydroxy, Amino, Amino, substituiert mit einem Alkyl mit 1 bis 5 Kohlenstoffatomen, Alkyl mit bis zu 10 Kohlenstoffatomen, Cycloalkyl mit bis zu 10 Kohlenstoffatomen, Alkoxy mit bis zu 10 Kohlenstoffatomen, Cycloalkoxy mit bis zu 10 Kohlenstoffatomen, Alkylidenmethyl mit bis zu 10 Kohlenstoffatomen, Cycloalkylidenmethyl mit bis zu 10 Kohlenstoffatomen, Phenyl oder Methylendioxy; (ii) Pyridin, substituiertes Pyridin, 2- oder 3-Pyrroliden, Imidazol, Naphtalin oder Thiophen; (iii) Cycloalkyl mit 4 bis 10 Kohlenstoffatomen ist, unsubstituiert oder substituiert mit einem oder mehreren Substituenten, jeweils unabhängig ausgewählt aus der Gruppe, bestehend aus Nitro, Cyano, Halo, Trifluormethyl, Carboethoxy, Carbomethoxy, Carbopropoxy, Acetyl, Carbamoyl, Acetoxy, Carboxy, Hydroxy, Amino, substituiertem Amino, Alkyl mit 1 bis 10 Kohlenstoffatomen, Alkoxy mit 1 bis 10 Kohlenstoffatomen, Phenyl;

jedes R⁴ und R⁵ einzeln genommen ein Wasserstoff ist oder R⁴ und R⁵ zusammen eine Kohlenstoff-Kohlenstoff-Bindung sind; wobei

Y CN ist;

R¹ R⁸, (CH₂)_nR⁸, OR⁸, CH=CHR⁸ oder CH=C(R¹⁰)₂ ist, mit der Maßgabe, daß R³ nicht unsubstituiertes Phenyl sein kann, wenn R¹ Methyl ist und R² Hydroxy ist;

R⁸ Methyl oder R⁹ ist;

R⁹ Alkyl mit 2 bis 10 Kohlenstoffatomen, Monocycloalkyl mit 3 bis 10 Kohlenstoffatomen, Polycycloalkyl mit bis zu 10 Kohlenstoffatomen, Benzocycloalkyl mit bis zu 10 Kohlenstoffatomen ist;

R¹⁰ zusammen mit dem Kohlenstoffatom, an das sie gebunden sind, eine Monocycloalkyloder Bicycloalkylgruppe mit bis zu 10 Kohlenstoffatomen bilden;

n 1 bis 3 ist;

oder, alternativ, wenn jedes von R⁴ und R⁵ einzeln genommen Wasserstoff ist;

Y -CON(R⁶)₂, -CO₂H, -CO₂R⁷ ist;

R¹ R⁹, -(CH₂)_nR⁸, -OR⁹, -CH=CHR⁸ oder -CH=C(R¹⁰)₂ ist;

R⁶ Wasserstoff oder Alkyl mit 1 bis 6 Kohlenstoffatomen ist;

R⁷ Alkyl mit 1 bis 6 Kohlenstoffatomen oder Benzyl ist; oder

Y COR⁷ ist;

R¹ R⁸, (CH₂)_nR⁸, OR⁸, CH=CHR⁸ oder CH=C(R¹⁰)₂ ist, mit der Maßgabe, daß R¹ und R² nicht -OMe sein können, wenn R³ Hydroxy-substituiertes Phenyl ist.

2. Verbindung nach Anspruch 1, dadurch gekennzeichnet, daß Y -CN oder COR⁷ ist; R¹ R⁸, (CH₂)_nR⁸, OR⁸ ist; R² Wasserstoff, Nitro, Cyano, Trifluormethyl, Carboethoxy, Carbomethoxy, Carbopropoxy, Acetyl, Carbamoyl, Acetoxy, Carboxy, Hydroxy, Amino, Alkyl mit 1 bis 6 Kohlenstoffatomen, Alkoxy mit 1 bis 6 Kohlenstoffatomen oder Halo ist.

3. Verbindung nach Anspruch 1, dadurch gekennzeichnet, daß Y -CONR⁶R⁶, CO₂H oder CO₂R⁷ ist; R¹ R⁹, (CH₂)_nR⁸, OR⁹ ist; R² Wasserstoff, Nitro, Cyano, Trifluormethyl, Carboethoxy, Carbomethoxy, Carbopropoxy, Acetyl, Carbamoyl, Acetoxy, Carboxy, Hydroxy, Amino, Alkyl mit 1 bis 6 Kohlenstoffatomen, Alkoxy mit 1 bis 6 Kohlenstoffatomen oder Halo ist.

4. Verbindung nach Anspruch 1, dadurch gekennzeichnet, daß R³ (i) Phenyl oder Naphtalin ist, substituiert oder unsubstituiert mit 1 oder mehr Substituenten, jeder unabhängig ausgewählt aus einer Gruppe, die aus Nitro, Cyano, Halo, Trifluormethyl, Carboethoxy, Carbomethoxy, Carbopropoxy, Acetyl, Carbamoyl oder Carbamoyl, substituiert mit Alkyl mit 1 bis 3 Kohlenstoffatomen, Acetoxy, Carboxy, Hydroxy, Amino, Amino, substituiert mit einem Alkyl mit 1 bis 5 Kohlenstoffatomen, Alkyl mit bis zu 10 Kohlenstoffatomen, Cycloalkyl mit bis zu 10 Kohlenstoffatomen, Alkoxy mit bis zu 10 Kohlenstoffatomen, Cycloalkoxy mit bis zu 10 Kohlenstoffatomen, Alkylidenmethyl mit bis zu 10 Kohlenstoffatomen, Cycloalkylidenmethyl mit bis zu 10 Kohlenstoffatomen, Phenyl oder Methylendioxy besteht; oder (ii) Cycloalkyl mit 4 bis 10 Kohlenstoffatomen, unsubstituiert oder substituiert, Nitro, Cyano, Halo, Trifluormethyl, Carboethoxy, Carbomethoxy, Carbopropoxy, Acetyl, Carbamoyl, Acetoxy, Carboxy, Hydroxy, Amino, substituiertes Amino, Alkyl mit 1 bis 10 Kohlenstoffatomen, Alkoxy mit 1 bis 10 Kohlenstoffatomen, Phenyl ist.

5. Verbindung nach Anspruch 1, dadurch gekennzeichnet, daß sie ein Nitril oder Keton der Formel ist:

oder

Y -CN oder -COR⁷ ist,

R¹ R⁸, (CH₂)_nR⁸, OR⁸, CH=CHR⁸ oder CH=C(R¹⁰)₂ ist;

R² Wasserstoff, Nitro, Cyano, Trifluormethyl, Carboethoxy, Carbomethoxy, Carbopropoxy, Acetyl, Carbamoyl, Acetoxy, Carboxy, Hydroxy, Amino, Alkyl mit 1 bis 6 Kohlenstoffatomen, Alkoxy mit 1 bis 6 Kohlenstoffatomen oder Halo ist;

R⁸ Methyl oder R⁹ ist;

R⁹ Alkyl mit 2 bis 10 Kohlenstoffatomen, Monocycloalkyl mit 3 bis 10 Kohlenstoffatomen, Polycycloalkyl mit bis zu 10 Kohlenstoffatomen, Benzocycloalkyl mit bis zu 10 Kohlenstoffatomen ist;

R¹⁰ zusammen mit dem Kohlenstoffätom, an das sie gebunden sind, eine Monocycloalkylgruppe bilden.

6. Verbindung nach Anspruch 1, dadurch gekennzeichnet, daß sie eine Carbonsäure, Ester oder Amid der Formel ist:

wobei:

Y -CO(NR⁶)₂, -CO₂H, -CO₂R⁷ ist;

R¹ R⁹, (CH₂)_nR⁸, OR⁹, CH=CHR⁸ oder CH=C(R¹⁰)₂ ist;

R⁶ Wasserstoff oder Alkyl mit 1 bis 6 Kohlenstoffatomen ist;

R⁷ Alkyl mit 1 bis 6 Kohlenstoffatomen oder Benzyl ist;

R⁸ Methyl oder R⁹ ist;

R⁹ Alkyl mit 2 bis 10 Kohlenstoffatomen, Monocycloalkyl mit 3 bis 10 Kohlenstoffatomen, Polycycloalkyl mit bis zu 10 Kohlenstoffatomen, Benzocycloalkyl mit bis zu 10 Kohlenstoffatomen ist;

R¹⁰ zusammen mit dem Kohlenstoffatom, an das sie gebunden sind, eine Monocycloalkyloder Bicycloalkylgruppe bilden; oder

n 1 bis 3 ist.

7. Verbindung nach Anspruch 1, dadurch gekennzeichnet, daß sie:

3,3 -Bis-(3,4-dimethoxyphenyl)acrylnitril,

3,3-Bis-(3-ethoxy-4-methoxyphenyl)acrylnitril,

3-(3-Propoxy-4-methoxyphenyl)-3-phenylacrylnitril,

3-(3-Ethoxy-4-methoxyphenyl)-3-phenylacrylnitril,

3,3-Bis-(3-cyclopentoxy-4-methoxyphenyl)acrylnitril,

3 -(3-Cyclopentoxy-4-methoxyphenyl)-3 -phenylacrylnitril,

3-(3-Cyclopentoxy-4-methoxyphenyl)-3-phenylpropannitril,

Methyl-3-(3-cyclopentoxy-4-methoxyphenyl)-3-phenylpropanoat,

3-(3-Ethoxy-4-methoxyphenyl)-3-phenylpropannitril,

Methyl-3-(3-ethoxy-4-methoxyphenyl)-3-phenylpropanoat,

3,3-Bis-(3,4-dimethoxyphenyl)propannitril,

3,3-Bis-(3-ethoxy-4-methoxyphenyl)propannitril,

3-(3,4-Dimethoxyphenyl)-3-phenylacrylnitril,

3-(3-Ethoxy-4-metoxyphenyl)-3-naphthylpropannitril,

3-(3,4-Dimethoxyphenyl)-3-phenylpropannitril oder

3-(3,4-Dimethoxyphenyl)-3-(3-ethoxy-4-methoxyphenyl)propannitril

ist.

8. Verbindung nach Anspruch 1, dadurch gekennzeichnet, daß sie:

4-(3-Ethoxy-4-methoxyphenyl)-4-(4-pyridyl)butan-2-on;

4-(3-Cyclopentoxy-4-methoxyphenyl)-4-(4-pyridyl)butan-2-on;

Methyl-3-(3-ethoxy-4-methoxyphenyl)-3-(4-pyridyl)propanoat;

3-(3-Ethoxy-4-methoxyphenyl)-3-(4-pyridyl)prop-2-ennitril;

3-(3-Ethoxy-4-methoxyphenyl)-3-(4-pyridyl)propannitril;

3-(3-Cyclopentoxy-4-methoxyphenyl)-3-(4-pyridyl)prop-2-ennitril;

3-(3-Cyclopentoxy-4-methoxyphenyl)-3-(4-pyridyl)propannitril;

4,4-Bis-(3,4-dimethoxyphenyl)butan-2-on;

4-(3,4-Dimethoxyphenyl)-4-(3-ethoxy-4-methoxyphenyl)butan-2-on;

4-(3,4-Dimethoxyphenyl)-4-(3-(cyclopentylidenmethyl)-4-methoxyphenyl)-butan-2-on;

3-(3,4-Dimethoxyphenyl)-3-(3-(cyclopentylidenmethyl)-4-methoxyphenyl)prop-2-ennitril;

3-(3-(Cyclopentylidenmethyl)-4-methoxyphenyl)-3-phenyl-prop-2-ennitril;

1-(3,4-Dimethoxyphenyl)-1-(3-ethoxy-4-methoxyphenyl)pentan-3-on;

1,1-Bis-(3,4-dimethoxyphenyl)pentan-3-on;

3-(3,4-Dimethoxyphenyl)-3-(3-(cyclopentylidenmethyl)-4-methoxyphenyl)prop-2-ennitril;

3-(3-(Cyclopentylidenmethyl)-4-methoxyphenyl)-3-phenyl-propannitril;

3,3-Bis-(3-(cyclopentylidenmethyl)-4-methoxyphenyl)propannitril;

3,3-Bis-(3-(cyclopentylidenmethyl)-4-methoxypenyl)prop-2-ennitril;

3-(3-(Cyclopentylidenmethyl)-4-methoxyphenyl-3-phenyl)propanamid;

3,3-Bis-(3-(cyclopentylidenmethyl)-4-methoxyphenyl)propanamid;

3,3-Bis-(3-ethoxy-4-methoxyphenyl)propanamid;

3,3-Bis-(3,4-dimethoxyphenyl)propanamid;

3-(3,4-Dimethoxyphenyl)-3-(4-methoxy-3-exo-norbomyloxyphenyl)prop-2-ennitril;

3-(3,4-Dimethoxyphenyl)-3-(3,4-methylendioxyphenyl)prop-2-ennitril;

3-(4-Aminophenyl)-3-(3,4-dimethoxyphenyl)prop-2-ennitril oder

3-(4-Aminophenyl)-3-(3-ethoxy-4-dimethoxyphenyl)prop-2-ennitril

ist.

9. Verbindung zur Verwendung als ein Immuntherapeutikum zur Verringerung von Cytokinspiegeln und Vorläufer der Formel:

in der:

R² Wasserstoff, Nitro, Cyano, Trifluormethyl, Carboethoxy, Carbomethoxy, Carbopropoxy, Acetyl, Carbamoyl, Acetoxy, Carboxy, Hydroxy, Amino, Alkyl mit 1 bis 6 Kohlenstoffatomen, Alkylidenmethyl mit 1 bis 6 Kohlenstoffatomen, Alkoxy mit 1 bis 6 Kohlenstoffatomen oder Halo ist; mit der Maßgabe, daß entweder R¹ ausgewählt ist aus einer Gruppe, die aus Alkoxy mit 1 bis 6 Kohlenstoffatomen, Cycloalkoxy mit von 3 bis 10 Kohlenstoffatomen und Cyclopentylidenmethyl besteht, und R² Alkoxy mit 1 bis 6 Kohlenstoffatomen ist; oder R³ Phenyl ist, unabhängig substituiert an den 3- und 4-Positionen mit Alkoxy mit bis zu 10 Kohlenstoffatomen oder Cycloalkoxy mit bis zu 10 Kohlenstoffatomen; und

R³ (i) Phenyl, substituiert oder unsubstituiert mit 1 oder mehr Substituenten, jeder unabhängig ausgewählt aus einer Gruppe, die aus Nitro, Cyano, Halo, Trifluormethyl, Carboethoxy, Carbomethoxy, Carbopropoxy, Acetyl, Carbamoyl oder Carbamoyl, substituiert mit Alkyl mit 1 bis 3 Kohlenstoffatomen, Acetoxy, Carboxy, Hydroxy, Amino, Amino, substituiert mit einem Alkyl mit 1 bis 5 Kohlenstoffatomen, Alkyl mit bis zu 10 Kohlenstoffatomen, Cycloalkyl mit bis zu 10 Kohlenstoffatomen, Alkoxy mit bis zu 10 Kohlenstoffatomen, Cycloalkoxy mit bis zu 10 Kohlenstoffatomen, Alkylidenmethyl mit bis zu 10 Kohlenstoffatomen, Cycloalkylidenmethyl mit bis zu 10 Kohlenstoffatomen, Phenyl oder Methylendioxy; (ii) Pyridin, substituiertes Pyridin, 2- oder 3-Pyrroliden, Imidazol, Naphtalin oder Thiophen; (iii) Cycloalkyl mit 4 bis 10 Kohlenstoffatomen ist, unsubstituiert oder substituiert mit einem oder mehreren Substituenten, jeweils unabhängig ausgewählt aus der Gruppe, bestehend aus Nitro, Cyano, Halo, Trifluormethyl, Caxboethoxyl Carbomethoxy, Carbopropoxy, Acetyl, Carbamoyl, Acetoxy, Carboxy, Hydroxy, Amino, substituiertem Amino, Alkyl mit 1 bis 10 Kohlenstoffatomen, Alkoxy mit I bis 10 Kohlenstoffatomen, Phenyl;

jedes R⁴ und R⁵ einzeln genommen ein Wasserstoff ist oder R⁴ und R⁵ zusammen eine Kohlenstoff-Kohlenstoff-Bindung sind; wobei

Y CN ist;

R¹ R⁸, (CH₂)_nR⁸, OR⁸, CH=CHR⁸ oder CH=C(R¹⁰)₂ ist, mit der Maßgabe, daß R³ nicht unsubstituiertes Phenyl sein kann, wenn R¹ Methyl ist und R² Hydroxy ist;

R⁸ Methyl oder R⁹ ist;

R⁹ Alkyl mit 2 bis 10 Kohlenstoffatomen, Monocycloalkyl mit 3 bis 10 Kohlenstoffatomen, Polycycloalkyl mit bis zu 10 Kohlenstoffatomen, Benzocycloalkyl mit bis zu 10 Kohlenstoffatomen ist;

R¹⁰ zusammen mit dem Kohlenstoffatom, an das sie gebunden sind, eine Monocycloalkyloder Bicycloalkylgruppe mit bis zu 10 Kohlenstoffatomen bilden,

n 1 bis 3 ist;

oder, alternativ, wenn jedes von R⁴ und R⁵ einzeln genommen Wasserstoff ist;

Y -CON(R⁶)₂, -CO₂H, -CO₂R⁷ ist;

R¹ R⁹, -(CH₂)_nR⁸, -OR⁹, -CH=CHR⁸ oder -CH=C(R¹⁰)₂ ist;

R⁶ Wasserstoff oder Alkyl mit 1 bis 6 Kohlenstoffatomen ist;

R⁷ Alkyl mit 1 bis 6 Kohlenstoffatomen oder Benzyl ist; oder

Y COR⁷ ist;

R¹ R⁸, (CH₂)_nR⁸, OR⁸, CH=CHR⁸ oder CH=C(R¹⁰)₂ ist, mit der Maßgabe, daß R¹ und R² nicht -OMe sein können, wenn R³ Hydroxy-substituiertes Phenyl ist.

10. Verbindung nach Anspruch 9, dadurch gekennzeichnet, daß Y -CN oder COR⁷ ist; R¹ R⁸, (CH₂)_nR⁸, OR⁸ ist; R² Wasserstoff, Nitro, Cyano, Trifluormethyl, Carboethoxy, Carbomethoxy, Carbopropoxy, Acetyl, Carbamoyl, Acetoxy, Carboxy, Hydroxy, Amino, Alkyl mit 1 bis 6 Kohlenstoffatomen, Alkoxy mit 1 bis 6 Kohlenstoffatomen oder Halo ist.

11. Verbindung nach Anspruch 9, dadurch gekennzeichnet, daß Y -CONR⁶R⁶, CO₂H oder CO₂R⁷ ist; R¹ R⁹, (CH₂)_nR⁸, OR⁹ ist; R² Wasserstoff, Nitro, Cyano, Trifluormethyl, Carboethoxy, Carbomethoxy, Carbopropoxy, Acetyl, Carbamoyl, Acetoxy, Carboxy, Hydroxy, Amino, Alkyl mit 1 bis 6 Kohlenstoffatomen, Alkoxy mit 1 bis 6 Kohlenstoffatomen oder Halo ist.

12. Verbindung nach Anspruch 9, dadurch gekennzeichnet, daß R³ (i) Phenyl oder Naphtalin ist, substituiert oder unsubstituiert mit 1 oder mehr Substituenten, jeder unabhängig ausgewählt aus einer Gruppe, die aus Nitro, Cyano, Halo, Trifluormethyl, Carboethoxy, Carbomethoxy, Carbopropoxy, Acetyl, Carbamoyl oder Carbamoyl, substituiert mit Alkyl mit 1 bis 3 Kohlenstoffatomen, Acetoxy, Carboxy, Hydroxy, Amino, Amino, substituiert mit einem Alkyl mit 1 bis 5 Kohlenstoffatomen, Alkyl mit bis zu 10 Kohlenstoffatomen, Cycloalkyl mit bis zu 10 Kohlenstoffatomen, Alkoxy mit bis zu 10 Kohlenstoffatomen, Cycloalkoxy mit bis zu 10 Kohlenstoffatomen, Alkylidenmethyl mit bis zu 10 Kohlenstoffatomen, Cycloalkylidenmethyl mit bis zu 10 Kohlenstoffatomen, Phenyl oder Methylendioxy besteht; oder (ii) Cycloalkyl mit 4 bis 10 Kohlenstoffatomen ist, unsubstituiert oder substituiert mit einem oder mehreren Substituenten, jeweils unabhängig ausgewählt aus der Gruppe, bestehend aus Nitro, Cyano, Halo, Trifluormethyl, Carboethoxy, Carbomethoxy, Carbopropoxy, Acetyl, Carbamoyl, Acetoxy, Carboxy, Hydroxy, Amino, substituiertem Amino, Alkyl mit 1 bis 10 Kohlenstoffatomen, Alkoxy mit 1 bis 10 Kohlenstoffatomen, Phenyl.

13. Verbindung nach Anspruch 9, dadurch gekennzeichnet, daß sie ein Nitril oder Keton der Formel ist:

oder

Y -CN oder -COR⁷ ist,

R¹ R⁸, (CH₂)_nR⁸, OR⁸, CH=CHR⁸ oder CH=C(R¹⁰)₂ ist;

R² Wasserstoff, Nitro, Cyano, Trifluormethyl, Carboethoxy, Carbomethoxy, Carbopropoxy, Acetyl, Carbamoyl, Acetoxy, Carboxy, Hydroxy, Amino, Alkyl mit 1 bis 6 Kohlenstoffatomen, Alkoxy mit 1 bis 6 Kohlenstoffatomen oder Halo ist;

R⁸ Methyl oder R⁹ ist;

R⁹ Alkyl mit 2 bis 10 Kohlenstoffatomen, Monocycloalkyl mit 3 bis 10 Kohlenstoffatomen, Polycycloalkyl mit bis zu 10 Kohlenstoffatomen, Benzocycloalkyl mit bis zu 10 Kohlenstoffatomen ist;

R¹⁰ zusammen mit dem Kohlenstoffatom, an das sie gebunden sind, eine Monocycloalkylgruppe bilden.

14. Verbindung nach Anspruch 9, dadurch gekennzeichnet, daß sie eine Carbonsäure, Ester oder Amid der Formel ist:

wobei:

Y -CO(NR⁶)₂, -CO₂H, -CO₂R⁷ ist;

R¹ R⁹, (CH₂)_nR⁸, OR⁹, CH=CHR⁸ oder CH=C(R¹⁰)₂ ist;

R⁶ Wasserstoff oder Alkyl mit 1 bis 6 Kohlenstoffatomen ist;

R⁷ Alkyl mit 1 bis 6 Kohlenstoffatomen oder Benzyl ist;

R⁸ Methyl oder R⁹ ist;

R⁹ Alkyl mit 2 bis 10 Kohlenstoffatomen, Monocycloalkyl mit 3 bis 10 Kohlenstoffatomen, Polycycloalkyl mit bis zu 10 Kohlenstoffatomen, Benzocycloalkyl mit bis zu 10 Kohlenstoffatomen ist;

R¹⁰ zusammen mit dem Kohlenstoffatom, an das sie gebunden sind, eine Monocycloalkyloder Bicycloalkylgruppe bilden; oder

n 1 bis 3 ist.

15. Verbindung nach Anspruch 9, dadurch gekennzeichnet, daß sie:

3,3-Bis-(3,4-dimethoxyphenyl)acrylnitril,

3,3-Bis-(3 -ethoxy-4-methoxyphenyl)acrylnitril,

3-(3-Propoxy-4-methoxyphenyl)-3-phenylacrylnitril,

3-(3-Ethoxy-4-methoxyphenyl)-3-phenylacrylnitril,

3,3-Bis-(3-cyclopentoxy-4-methoxyphenyl)acrylnitril,

3-(3-Cyclopentoxy-4-methoxyphenyl)-3-phenylacrylnitril,

3-(3-Cyclopentoxy-4-methoxyphenyl)-3-phenylpropannitril,

Methyl-3-(3-cyclopentoxy-4-methoxyphenyl)-3-phenylpropanoat,

3-(3-Ethoxy-4-methoxyphenyl)-3-phenylpropannitril,

Methyl-3-(3-ethoxy-4-methoxyphenyl)-3-phenylpropanoat,

3,3-Bis-(3,4-dimethoxyphenyl)propannitril,

3,3-Bis-(3-ethoxy-4-methoxyphenyl)propannitril,

3-(3,4-Dimethoxyphenyl)-3-phenylacrylnitril,

3-(3-Ethoxy-4-methoxyphenyl)-3-naphthylpropannitril,

3-(3,4-Dimethoxyphenyl)-3-phenylpropaimitril oder

3-(3,4-Dimethoxyphenyl)-3-(3-ethoxy-4-methoxyphenyl)propannitril

ist.

16. Verbindung nach Anspruch 9, dadurch gekennzeichnet, daß sie:

4-(3-Ethoxy-4-methoxyphenyl)-4-(4-pyridyl)butan-2-on;

4-(3-Cyclopentoxy-4-methoxyphenyl)-4-(4-pyridyl)butan-2-on;

Methyl-3 -(3-ethoxy-4-methoxyphenyl)-3-(4-pyridyl)propanoat;

3-(3-Ethoxy-4-methoxyphenyl)-3-(4-pyridyl)prop-2-ennitril;

3-(3-Ethoxy-4-methoxyphenyl)-3-(4-pyridyl)propannitril;

3-(3-Cyclopentoxy-4-methoxyphenyl)-3-(4-pyridyl)prop-2-ennitril;

3-(3-Cyclopentoxy-4-methoxyphenyl)-3-(4-pyridyl)propannitril;

4,4-Bis-(3,4-dimethoxyphenyl)butan-2-on;

4-(3,4-Dimethoxyphenyl)-4-(3-ethoxy-4-methoxyphenyl)butan-2-on;

4-(3,4-Dimethoxyphenyl)-4-(3-(cyclopentylidenmethyl)-4-methoxyphenyl)-butan-2-on;

3-(3,4-Dimethoxyphenyl)-3-(3-(cyclopentylidemnethyl)-4-methoxyphenyl)prop-2-ennitril;

3-(3-(Cyclopentylidenmethyl)-4-methoxyphenyl)-3-phenyl-prop-2-ermitril;

1-(3,4-Dimethoxyphenyl)-1-(3-ethoxy-4-methoxyphenyl)pentan-3-on;

1,1-Bis-(3,4-dimethoxyphenyl)pentan-3-on;

3-(3,4-Dimethoxyphenyl)-3-(3-(cyclopentylidenmethyl)-4-methoxyphenyl)prop-2-ennitril;

3-(3-(Cyclopentylidenmethyl)-4-methoxyphenyl)-3-phenyl-propannitril;

3,3 -Bis-(3 -(cyclopentylidenmmethyl)-4-methoxyphenyl)propannitril;

3,3-Bis-(3-(cyclopentylidenmethyl)-4-methoxypenyl)prop-2-ennitril;

3-(3-(Cyclopentylidenmethyl)-4-methoxyphenyl-3-phenyl)propanamid;

3,3-Bis-(3-(cyclopentylidenmethyl)-4-methoxyphenyl)propanamid;

3,3-Bis-(3-ethoxy-4-methoxyphenyl)propanamid;

3,3-Bis-(3,4-dimethoxyphenyl)propanamid;

3-(3,4-Dimethoxyphenyl)-3-(4-methoxy-3-exo-norbomyloxyphenyl)prop-2-ennitril;

3-(3,4-Dimethoxyphenyl)-3-(3,4-methylendioxyphenyl)prop-2-ennitril;

3-(4-Aminophenyl)-3-(3,4-dimethoxyphenyl)prop-2-ennitril oder

3-(4-Aminophenyl)-3-(3-ethoxy-4-dimethoxyphenyl)prop-2-ennitril

ist.

Revendications

1. Composé de formule ;

où :

R² est l'hydrogène, nitro, cyano, trifluorométhyle, carboéthoxy, carbométhoxy, carbopropoxy, acétyle, carbamoyle, acétoxy, carboxyle, hydroxyle, amino, alkyle de 1 à 6 atomes de carbone, alkylidèneméthyle de 1 à 6 atomes de carbone, alcoxy de 1 à 6 atomes de carbone ou halogéno ; avec la condition que R¹ est choisi dans un groupe consistant en alcoxy de 1 à 6 atomes de carbone, cycloalcoxy de 3 à 10 atomes de carbone et cyclopentylidèneméthyle et R² est alcoxy de 1 à 6 atomes de carbone ; ou bien R³ est phényle indépendamment substitué aux positions 3 et 4 par alcoxy de jusqu'à 10 atomes de carbone ou cycloalcoxy de jusqu'à 10 atomes de carbone ; et

R³ est (i) phényle substitué ou non substitué par un ou plusieurs substituants choisis chacun indépendamment dans un groupe consistant en nitro, cyano, halogéno, trifluorométhyle, carboéthoxy, carbométhoxy, carbopropoxy, acétyle, carbamoyle ou carbamoyle substitué par alkyle de 1 à 3 atomes de carbone, acétoxy, carboxyle, hydroxyle, amino, amino substitué par un alkyle de 1 à 5 atomes de carbone, alkyle de jusqu'à 10 atomes de carbone, cydoalkyle de jusqu'à 10 atomes de carbone, alcoxy de jusqu'à 10 atomes de carbone, cydoalcoxy de jusqu'à 10 atomes de carbone, alkylidèneméthyle de jusqu'à 10 atomes de carbone, cycloalkylidèneméthyle de jusqu'à 10 atomes de carbone, phényle ou méthylènedioxy ; (ii) pyridine, pyridine substituée, 2- ou 3-pyrrolidène, imidazole, naphtalène ou thiophène ; (iii) cycloalkyle de 4 à 10 atomes de carbone non substitué ou substitué, nitro, cyano, halogéno, trifluorométhyle, carboéthoxy, carbométhoxy, carbopropoxy, acétyle, carbamoyle, acétoxy, carboxyle, hydroxyle, amino, amino substitué, alkyle de 1 à 10 atomes de carbone, alcoxy de 1 à 10 atomes de carbone, phényle ;

R⁴ et R⁵ sont chacun individuellement l'hydrogène ou bien R⁴ et R⁵ sont ensemble une liaison carbone-carbone ; où

Y est CN ;

R¹ est R⁸, (CH₂)_nR⁸, OR⁸, CH=CHR⁸ ou CH=C(R¹⁰)₂ avec la condition que R³ ne peut pas être phényle non substitué quand R¹ est méthyle et R² est hydroxyle ;

R⁸ est méthyle ou R⁹ ;

R⁹ est alkyle de 2 à 10 atomes de carbone, monocydoalkyle de 3 à 10 atomes de carbone, polycycloalkyle de jusqu'à 10 atomes de carbone, benzocycloalkyle de jusqu'à 10 atomes de carbone ;

les R¹⁰ forment avec l'atome de carbone auquel ils sont liés un groupe monocycloalkyle ou bicycloalkyle de jusqu'à 10 atomes de carbone ;

n est 1 à 3 ;

ou bien, à titre d'alternative, quand R⁴ et R⁵ pris individuellement sont chacun l'hydrogène ;

Y est -CON(R⁶)₂, -CO₂H, -CO₂R⁷ ;

R¹ est R⁹, -(CH₂)_nR⁸, -OR⁹, -CH=CHR⁸ ou -CH=C(R¹⁰)₂;

R⁶ est l'hydrogène ou alkyle de 1 à 6 atomes de carbone ;

R⁷ est alkyle de 1 à 6 atomes de carbone ou benzyle ; ou

Y est COR⁷ ;

R¹ est -R⁸, (CH₂)_nR⁸, OR⁸, CH=CHR⁸ ou CH=C(R¹⁰)₂, avec la condition que R¹ et R² ne peuvent pas être -OMe quand R³ est phényle hydroxy-substitué.

2. Composé selon la revendication 1 où Y est -CN ou COR⁷ ; R¹ est R⁸, (CH₂)_nR⁸, OR⁸ ; R² est l'hydrogène, nitro, cyano, trifluorométhyle, carboéthoxy, carbométhoxy, carbopropoxy, acétyle, carbamoyle, acétoxy, carboxyle, hydroxyle, amino, alkyle de 1 à 6 atomes de carbone, alcoxy de 1 à 6 atomes de carbone ou halogéno.

3. Composé selon la revendication 1, où Y est -CONR⁶R⁶, CO₂H ou CO₂R⁷ ; R¹ est R⁹, (CH₂)_nR⁸, OR⁹ ; R² est l'hydrogène, nitro, cyano, trifluorométhyle, carboéthoxy, carbométhoxy, carbopropoxy, acétyle, carbamoyle, acétoxy, carboxyle, hydroxyle, amino, alkyle de 1 à 6 atomes de carbone, alcoxy de 1 à 6 atomes de carbone ou halogéno.

4. Composé selon la revendication 1, où R³ est (i) phényle ou naphtalène, substitué ou non substitué par un ou plusieurs substituants choisis chacun indépendamment dans un groupe consistant en nitro, cyano, halogéno, trifluorométhyle, carboéthoxy, carbométhoxy, carbopropoxy, acétyle, carbamoyle ou carbamoyle substitué par alkyle de 1 à 3 atomes de carbone, acétoxy, carboxyle, hydroxyle, amino, amino substitué par un alkyle de 1 à 5 atomes de carbone, alkyle de jusqu'à 10 atomes de carbone, cycloalkyle de jusqu'à 10 atomes de carbone, alcoxy de jusqu'à 10 atomes de carbone, cydoalcoxy de jusqu'à 10 atomes de carbone, alkylidèneméthyle de jusqu'à 10 atomes de carbone; cydoalkylldèneméthyle de jusqu'à 10 atomes de carbone, phényle ou méthylènedioxy ; ou (ii) cycloalkyle de 4 à 10 atomes de carbone non substitué ou substitué, nitro, cyano, halogéno, trifluorométhyle, carboéthoxy, carbométhoxy, carbopropoxy, acétyle, carbamoyle, acétoxy, carboxyle, hydroxyle, amino, amino substitué, alkyle de 1 à 10 atomes de carbone, alcoxy de 1 à 10 atomes de carbone, phényle.

5. Composé selon la revendication 1 qui est un nitrile ou une cétone de formule :

   ou

Y est -CN ou -COR⁷,

R¹ est R⁸, (CH₂)_nR⁸, OR⁸, CH=CHR⁸ ou CH=C(R¹⁰)₂ ;

R² est l'hydrogène, nitro, cyano, trifluorométhyle, carboéthoxy, carbométhoxy, carbopropoxy, acétyle, carbamoyte, acétoxy, carboxyle, hydroxyle, amino, alkyle de 1 à 6 atomes de carbone, alcoxy de 1 à 6 atomes de carbone ou halogéno;

R⁸ est méthyle ou R⁹ ;

R⁹ est alkyle de 2 à 10 atomes de carbone, monocydoalkyle de 3 à 10 atomes de carbone, polycycloalkyle de jusqu'à 10 atomes de carbone, benzocycloalkyle de jusqu'à 10 atomes de carbone ;

les R¹⁰ forment avec l'atome de carbone auquel ils sont liés un groupe monocycloalkyle.

6. Composé selon la revendication 1, qui est un acide, ester ou amide carboxylique de formule :

   où :

Y est -CO(NR⁶)₂, -CO₂H, -CO₂R⁷ ;

R¹ est R⁹, (CH₂)_nR⁸, OR⁹, CH=CHR⁸ ou CH=C(R¹⁰)₂;

R⁶ est l'hydrogène ou alkyle de 1 à 6 atomes de carbone ;

R⁷ est alkyle de 1 à 6 atomes de carbone ou benzyle ;

R⁸ est méthyle ou R⁹ ;

R⁹ est alkyle de 2 à 10 atomes de carbone, monocydoalkyle de 3 à 10 atomes de carbone, polycydoalkyle de jusqu'à 10 atomes de carbone, benzocycloalkyle de jusqu'à 10 atomes de carbone ;

les R¹⁰ forment avec l'atome de carbone auquel ils sont liés un groupe monocycloalkyle ou bicydoalkyle ; ou

n est 1 à 3.

7. Composé selon la revendication 1 qui est :

le 3,3-bis-(3,4-diméthoxyphényl)acrylonitrile,

le 3,3-bis-(3-éthoxy-4-méthoxyphényl)acrylonitrile,

le 3-(3-propoxy-4-méthoxyphényl)-3-phénylacrylonitrile,

le 3-(3-éthoxy-4-méthoxyphényl)-3-phénylacrylonitrile,

le 3,3-bis-(3-cyclopentoxy-4-méthoxyphényl)acrylonitrile,

le 3-(3-cyclopentoxy-4-méthoxyphényl)-3-phénylacrylonitrile,

le 3-(3-cyclopentoxy-4-méthoxyphényl)-3-phénylpropanenitrile,

le 3-(3-cyclopentoxy-4-méthoxyphényl)-3-phénylpropanoate de méthyle,

le 3-(3-éthoxy-4-méthoxyphényl)-3-phénylpropanenitrile,

le 3-(3-éthoxy-4-méthoxyphényl)-3-phénylpropanoate de méthyle,

le 3,3-bis-(3,4-diméthoxyphényl)propanenitrile,

le 3,3-bis-(3-éthoxy-4-méthoxyphényl)propanenitrile,

le 3-(3,4-diméthoxyphényl)-3-phénylacrylonitrile,

le 3-(3-éthoxy-4-méthoxyphényl)-3-naphtylpropanenitrile,

le 3-(3,4-diméthoxyphényl)-3-phényipropanenitrile, ou

le 3-(3,4-diméthoxyphényl)-3-(3-éthoxy-4-méthoxyphényl)propanenitrile.

8. Composé selon la revendication 1, qui est :

la 4-(3-éthoxy-4-méthoxyphényl)-4-(4-pyridyl)butan-2-one ;

la 4-(3-cyclopentoxy-4-méthoxyphényl)-4-(4-pyridyl)butan-2-one ;

le 3-(3-éthoxy-4-méthoxyphényl)-3-(4-pyridyl)propanoate de méthyle ;

le 3-(3-éthoxy-4-méthoxyphényl)-3-(4-pyridyl)prop-2-ènenitrile;

le 3-(3-éthoxy-4-méthoxyphényl)-3-(4-pyridyl)propanenitrile ;

le 3-(3-cyclopentoxy-4-méthoxyphényl)-3-(4-pyridyl)prop-2-ènenitrite ;

le 3-(3-cyclopentoxy-4-méthoxyphényl)-3-(4-pyridyl)propanenitrile ;

la 4,4-bis-(3,4-diméthoxyphényl)butan-2-one ;

la 4-(3,4-diméthoxyphényl)-4-(3-éthoxy-4-méthoxyphényl)butan-2-one ;

la 4-(3,4-diméthoxyphényl)-4-(3-(cyclopentylidèneméthyl)-4-méthoxyphényl)butan-2-one ;

le 3-(3,4-diméthoxyphényl)-3-(3-(cyclopentylidèneméthyl)-4-méthoxyphényl)prop-2-ènenitrile ;

le 3-(3-(cyclopentylidèneméthyl)-4-méthoxyphényl)-3-phényl-prop-2-ènenitrile ;

la 1-(3,4-diméthoxyphényl)-1-(3-éthoxy-4-méthoxyphényl)pentan-3-one ;

la 1,1-bis-(3,4-diméthoxyphényl)pentan-3-one ;

le 3-(3,4-diméthoxyphényl)-3-(3-(cyclopentylidèneméthyl)-4-méthoxyphényl)prop-2-ènenitrile ;

le 3-(3-(cyclopentylidèneméthyl)-4-méthoxyphényl)-3-phénylpropanenitrile ;

le 3,3-bis-(3-(cyclopentylidèneméthyl)-4-méthoxyphényl)propanenitrile ;

le 3,3-bis-(3-(cyclopentylidèneméthyl)-4-méthoxyphényl)prop-2-ènenitrile ;

le 3-(3-(cydopentylidèneméthyl)-4-méthoxyphényl-3-phényl)propanamide ;

le 3,3-bis-(3-(cyclopentylidèneméthyl)-4-méthoxyphényl)propanamide ;

le 3,3-bis-(3-éthoxy-4-méthoxyphényl)propanamide ;

le 3,3-bis-(3,4-diméthoxyphényl)propanamide ;

le 3-(3,4-diméthoxyphényl)-3-(4-méthoxy-3-exo-norbornyloxyphényl)prop-2-ènenitrile ;

le 3-(3,4-diméthoxyphényl)-3-(3,4-méthylènedioxyphényl)prop-2-ènenitrile ;

le 3-(4-aminophényl)-3-(3,4-diméthoxyphényl)prop-2-ènenitrile ; ou

le 3-(4-aminophényl)-3-(3-éthoxy-4-diméthoxyphényl)prop-2-ènenitrile.

9. Composé destiné à être utilisé comme agent immunothérapeutique pour la réduction des niveaux de cytokines et précurseurs de formule :

où:

R² est l'hydrogène, nitro, cyano, trifluorométhyle, carboéthoxy, carbométhoxy, carbopropoxy, acétyle, carbamoyle, acétoxy, carboxyle, hydroxyle, amino, alkyle de 1 à 6 atomes de carbone, alkylidèneméthyle de 1 à 6 atomes de carbone, alcoxy de 1 à 6 atomes de carbone ou halogéno ; avec la condition que R¹ est choisi dans un groupe consistant en alcoxy de 1 à 6 atomes de carbone, cycloalcoxy de 3 à 10 atomes de carbone et cyclopentylidèneméthyle et R² est alcoxy de 1 à 6 atomes de carbone ; ou bien R³ est phényle indépendamment substitué aux positions 3 et 4 par alcoxy de jusqu'à 10 atomes de carbone ou cycloalcoxy de jusqu'à 10 atomes de carbone ; et

R³ est (i) phényle substitué ou non substitué par un ou plusieurs substituants choisis chacun indépendamment dans un groupe consistant en nitro, cyano, halogéno, trifluorométhyle, carboéthoxy, carbométhoxy, carbopropoxy, acétyle, carbamoyle ou carbamoyle substitué par alkyle de 1 à 3 atomes de carbone, acétoxy, carboxyle, hydroxyle, amino, amino substitué par un alkyle de 1 à 5 atomes de carbone, alkyle de jusqu'à 10 atomes de carbone, cycloalkyle de jusqu'à 10 atomes de carbone, alcoxy de jusqu'à 10 atomes de carbone, cydoalcoxy de jusqu'à 10 atomes de carbone, alkylidèneméthyle de jusqu'à 10 atomes de carbone, cycloalkylidèneméthyle de jusqu'à 10 atomes de carbone, phényle ou méthylènedioxy ; (ii) pyridine, pyridine substituée, 2- ou 3-pyrrolidène, imidazole, naphtalène ou thiophène ; (iii) cycloalkyle de 4 à 10 atomes de carbone non substitué ou substitué, nitro, cyano, halogéno, trifluorométhyle, carboéthoxy, carbométhoxy, carbopropoxy, acétyle, carbamoyle, acétoxy, carboxyle, hydroxyte, amino, amino substitué, alkyle de 1 à 10 atomes de carbone, alcoxy de 1 à 10 atomes de carbone, phényle ;

R⁴ et R⁵ sont chacun individuellement l'hydrogène ou bien R⁴ et R⁵ sont ensemble une liaison carbone-carbone ; où

Y est CN ;

R¹ est R⁸, (CH₂)_nR⁸, OR⁸, CH=CHR⁸ ou CH=C(R¹⁰)₂ avec la condition que R³ ne peut pas être phényle non substitué quand R¹ est méthyle et R² est hydroxyle ;

R⁸ est méthyle ou R⁹ ;

R⁹ est alkyle de 2 à 10 atomes de carbone, monocydoalkyle de 3 à 10 atomes de carbone, polycydoelkyle de jusqu'à 10 atomes de carbone, benzocycloalkyle de jusqu'à 10 atomes de carbone ;

les R¹⁰ forment avec l'atome de carbone auquel ils sont liés un groupe monocycloalkyle ou bicycloalkyle de jusqu'à 10 atomes de carbone ;

n est 1 à 3 ;

ou bien, à titre d'alternative, quand R⁴ et R⁵ pris individuellement sont chacun l'hydrogène ;

Y est -CON(R⁶)₂, -CO₂H, -CO₂R⁷ ;

R¹ est R⁹, -(CH₂)_nR⁸, -OR⁹, -CH=CHR⁸ ou -CH=C(R¹⁰)₂ ;

R⁶ est l'hydrogène ou alkyle de 1 à 6 atomes de carbone ;

R⁷ est alkyle de 1 à 6 atomes de carbone ou benzyle ; ou

Y est COR⁷ ;

R¹ est -R⁸, (CH₂)_nR⁸, OR⁸, CH=CHR⁸ ou CH=C(R¹⁰)₂, avec la condition que R¹ et R² ne peuvent pas être -OMe quand R³ est phényle hydroxy-substitué.

10. Composé selon la revendication 9, où Y est -CN ou COR⁷ ; R¹ est R⁸, (CH₂)_nR⁸, OR⁸ ; R² est l'hydrogène, nitro, cyano, trifluorométhyle, carboéthoxy, carbométhoxy, carbopropoxy, acétyle, carbamoyle, acétoxy, carboxyle, hydroxyle, amino, alkyle de 1 à 6 atomes de carbone, alcoxy de 1 à 6 atomes de carbone ou halogéno.

11. Composé selon la revendication 9, où Y est -CONR⁶R⁶, CO₂H ou CO₂R⁷ ; R¹ est R⁹, (CH₂)_nR⁸, OR⁹ ; R² est l'hydrogène, nitro, cyano, trifluorométhyle, carboéthoxy, carbométhoxy, carbopropoxy, acétyle, carbamoyle, acétoxy, carboxyle, hydroxyle, amino, alkyle de 1 à 6 atomes de carbone, alcoxy de 1 à 6 atomes de carbone ou halogéno.

12. Composé selon la revendication 9, où R³ est (i) phényle ou naphtalène, substitué ou non substitué par un ou plusieurs substituants choisis chacun indépendamment dans un groupe consistant en nitro, cyano, halogéno, trifluorométhyle, carboéthoxy, carbométhoxy, carbopropoxy, acétyle, carbamoyle ou carbamoyle substitué par alkyle de 1 à 3 atomes de carbone, acétoxy, carboxyle, hydroxyle, amino, amino substitué par un alkyle de 1 à 5 atomes de carbone, alkyle de jusqu'à 10 atomes de carbone, cycloalkyle de jusqu'à 10 atomes de carbone, alcoxy de jusqu'à 10 atomes de carbone, cycloalcoxy de jusqu'à 10 atomes de carbone, alkylidèneméthyle de jusqu'à 10 atomes de carbone, cycloalkylidèneméthyle de jusqu'à 10 atomes de carbone, phényle ou méthylènedioxy ; ou (il) cycloelkyle de 4 à 10 atomes de carbone non substitué ou substitué, nitro, cyano, halogéno, trifluorométhyle, carboéthoxy, carbométhoxy, carbopropoxy, acétyle, carbamoyle, acétoxy, carboxyle, hydroxyle, amino, amino substitué, alkyle de 1 à 10 atomes de carbone, alcoxy de 1 à 10 atomes de carbone, phényle.

13. Composé selon la revendication 9, qui est un nitrile ou une cétone de formule :

   ou

Y est -CN ou -COR⁷,

R¹ est R⁸, (CH₂)_nR⁸, OR⁸, CH=CHR⁸ ou CH=C(R¹⁰)₂ ;

R² est l'hydrogène, nitro, cyano, trifluorométhyle, carboéthoxy, carbométhoxy, carbopropoxy, acétyle, carbamoyle, acétoxy, carboxyle, hydroxyle, amino, alkyle de 1 à 6 atomes de carbone, alcoxy de 1 à 6 atomes de carbone ou halogéno ;

R⁸ est méthyle ou R⁹ ;

R⁹ est alkyle de 2 à 10 atomes de carbone, monocycloalkyle de 3 à 10 atomes de carbone, polycycloalkyle de jusqu'à 10 atomes de carbone, benzocycloalkyle de jusqu'à 10 atomes de carbone ;

les R¹⁰ forment avec l'atome de carbone auquel ils sont liés un groupe monocycloalkyle.

14. Composé selon la revendication 9, qui est un acide, ester ou amide carboxylique de formule :

où :

Y est -CO(NR⁶)₂, -CO₂H, -CO₂R⁷ ;

R¹ est R⁹, (CH₂)_nR⁸, OR⁹, CH=CHR⁸ ou CH=C(R¹⁰)₂ ;

R⁶ est l'hydrogène ou alkyle de 1 à 6 atomes de carbone ;

R⁷ est alkyle de 1 à 6 atomes de carbone ou benzyle ;

R⁸ est méthyle ou R⁹ ;

R⁹ est alkyle de 2 à 10 atomes de carbone, monocycloalkyle de 3 à 10 atomes de carbone, polycycloalkyle de jusqu'à 10 atomes de carbone, benzocycloalkyle de jusqu'à 10 atomes de carbone ;

les R¹⁰ forment avec l'atome de carbone auquel ils sont liés un groupe monocycloalkyle ou bicycloalkyle ; ou

n est 1 à 3.

15. Composé selon la revendication 9, qui est :

le 3,3-bis-(3,4-diméthoxyphényl)acrylonitrile,

le 3,3-bis-(3-éthoxy-4-méthoxyphényl)acrylonitrile,

le 3-(3-propoxy-4-méthoxyphényl)-3-phénylacrylonitrile,

le 3-(3-éthoxy-4-méthoxyphényl)-3-phénylacrylonitrile,

le 3,3-bis-(3-cyclopentoxy-4-méthoxyphényl)acrylonitrile,

le 3-(3-cyctopentoxy-4-méthoxyphényl)-3-phénylacrylonitrile,

le 3-(3-cyclopentoxy-4-méthoxyphényl)-3-phénylpropanenitrile,

le 3-(3-cyclopentoxy-4-méthoxyphényl)-3-phénylpropanoate de méthyle,

le 3-(3-éthoxy-4-méthoxyphényl)-3-phénylpropanenitrile,

le 3-(3-éthoxy-4-méthoxyphényl)-3-phénylpropanoate de méthyle,

le 3,3-bis-(3,4-diméthoxyphényl)propanenitrile,

le 3,3-bis-(3-éthoxy-4-méthoxyphényl)propanenitrile,

le 3-(3,4-diméthoxyphényl)-3-phénylacrylonitrile,

le 3-(3-éthoxy-4-méthoxyphényl)-3-naphtylpropanenitrile,

le 3-(3,4-diméthoxyphényl)-3-phénylpropanenitrile, ou

le 3-(3,4-diméthoxyphényl)-3-(3-éthoxy-4-méthoxyphényl)propanenitrile.

16. Composé selon la revendication 9, qui est :

la 4-(3-éthoxy-4-méthoxyphényl)-4-(4-pyridyl)butan-2-one ;

la 4-(3-cyclopentoxy-4-méthoxyphényl)-4-(4-pyridyl)butan-2-one ;

le 3-(3-éthoxy-4-méthoxyphényl)-3-(4-pyridyl)propanoate de méthyle ;

le 3-(3-éthoxy-4-méthoxyphényl)-3-(4-pyridyl)prop-2-ènenitrile ;

le 3-(3-éthoxy-4-méthoxyphényl)-3-(4-pyridyl)propanenltrile ;

le 3-(3-cyclopentoxy-4-méthoxyphényl)-3-(4-pyridyl)prop-2-ènenitrile ;

le 3-(3-cyclopentoxy-4-méthoxyphényl)-3-(4-pyridyl)propanenitrile ;

la 4,4-bis-(3,4-diméthoxyphényl)butan-2-one ;

la 4-(3,4-diméthoxyphényl)-4-(3-éthoxy-4-méthoxyphényl)butan-2-one ;

la 4-(3,4-diméthoxyphényl)-4-(3-(cyclopentylidèneméthyl)-4-méthoxyphényl)butan-2-one ;

le 3-(3,4-diméthoxyphényl)-3-(3-(cyclopentylidèneméthyl)-4-méthoxyphényl)prop-2-ènenitrile ;

le 3-(3-(cyclopentylidèneméthyl)-4-méthoxyphényl)-3-phényl-prop-2-ènenitrile ;

la 1-(3,4-diméthoxyphényl)-1-(3-éthoxy-4-méthoxyphényl)pentan-3-one ;

la 1,1-bis-(3,4-diméthoxyphényl)pentan-3-one ;

le 3-(3,4-diméthoxyphényl)-3-(3-(cyclopentylidèneméthyl)-4-méthoxyphényl)prop-2-ènenitrile ;

le 3-(3-(cyclopentylidèneméthyl)-4-méthoxyphényl)-3-phénylpropanenitrile ;

le 3,3-bis-(3-(cyclopentylidèneméthyl)-4-méthoxyphényl)propanenitrile ;

le 3,3-bis-(3-(cyclopentylidèneméthyl)-4-méthoxyphényl)prop-2-ènenitrile ;

le 3-(3-(cydopentylidèneméthyl)-4-méthoxyphényl-3-phényl)propanamide ;

le 3,3-bis-(3-(cyclopentylidèneméthyl)-4-méthoxyphényl)propanamide ;

le 3,3-bis-(3-éthoxy-4-méthoxyphényl)propanamide ;

le 3,3-bis-(3,4-diméthoxyphényl)propanamide ;

le 3-(3,4-dlméthoxyphényl)-3-(4-méthoxy-3-exo-norbornyloxyphényl)prop-2-ènenitrile ;

le 3-(3,4-diméthoxyphényl)-3-(3,4-méthylènedioxyphényl)prop-2-ènenitrile ;

le 3-(4-aminophényl)-3-(3,4-diméthoxyphényl)prop-2-ènenitrile ; ou

le 3-(4-aminophényl)-3-(3-éthoxy-4-diméthoxyphényl)prop-2-ènenitrile.